Mieszana choroba tkanki łącznej
Patofizjologia i mechanizm

Mieszana choroba tkanki łącznej (MCTD) to rzadka, układowa choroba autoimmunologiczna charakteryzująca się wysokim mianem przeciwciał anty-U1-RNP, szczególnie skierowanych przeciwko podjednostce 70 kDa kompleksu U1-RNP. Patogeneza MCTD obejmuje złożone mechanizmy immunologiczne, w tym bezpośrednie wiązanie autoprzeciwciał z komórkami śródbłonka, tworzenie kompleksów immunologicznych aktywujących kaskadę dopełniacza oraz stymulację limfocytów CD4+ do produkcji IL-1 i IL-6. Kluczową rolę odgrywają modyfikacje apoptotyczne białka U1-70kDa, które prowadzą do przełamania tolerancji immunologicznej, oraz aktywacja receptorów Toll-podobnych (TLR3, TLR7), co indukuje produkcję interferonów typu I (IFN-I) i IFN-γ, nasilając autoimmunizację. Genetycznie MCTD jest powiązana z allelami HLA-DRB1*04:01 i HLA-B*08, różniąc się od innych chorób tkanki łącznej, a polimorfizmy genów interferonowych i mikroRNA (np. miR-146a rs2910164) wpływają na podatność i fenotyp kliniczny choroby.

  1. Patogeneza mieszanej choroby tkanki łącznej
    1. Rola przeciwciał anty-U1-RNP w patogenezie
    2. Mechanizmy patogenne przeciwciał anty-U1-RNP
    3. Rola apoptozy w patogenezie MCTD
    4. Predyspozycje genetyczne do MCTD
    5. Rola receptorów Toll-podobnych w patogenezie MCTD
    6. Rola interferonów w patogenezie MCTD
    7. Rola limfocytów T i B w patogenezie
    8. Zmiany naczyniowe w MCTD
    9. Metylacja DNA w patogenezie MCTD
    10. Rola mikroRNA w patogenezie MCTD
  2. Model zwierzęcy MCTD
  3. Implikacje kliniczne patogenezy dla manifestacji choroby
  4. Wnioski i przyszłe kierunki badań
    1. Kolejne rozdziały

Patogeneza mieszanej choroby tkanki łącznej

Mieszana choroba tkanki łącznej (MCTD) jest rzadką układową chorobą autoimmunologiczną, charakteryzującą się nakładającymi się objawami co najmniej dwóch chorób tkanki łącznej, w tym tocznia rumieniowatego układowego (SLE), twardziny układowej, zapalenia wielomięśniowego, zapalenia skórno-mięśniowego i reumatoidalnego zapalenia stawów. Patogeneza MCTD pozostaje nie w pełni wyjaśniona, jednak w ostatnich latach poczyniono znaczący postęp w zrozumieniu mechanizmów immunologicznych leżących u podstaw tej choroby.12

Rola przeciwciał anty-U1-RNP w patogenezie

Głównym markerem serologicznym MCTD są wysokie miana przeciwciał przeciwko rybonukleoproteinie U1 (anty-U1-RNP). Te przeciwciała są skierowane przeciwko kompleksowi U1-RNP, który jest wewnątrzjądrowym białkiem przekształcającym pre-mRNA w dojrzałe RNA. Kompleks U1-RNP składa się z trzech specyficznych białek: A, C i 70 kDa, do których wiążą się przeciwciała anty-U1-RNP. Antygen 70 kDa jest głównym celem przeciwciał anty-RNP w MCTD i odgrywa centralną rolę w patogenezie choroby.34

Badania wykazały, że peptyd 70-kD białka U1-RNP stanowi dominujący autoantygen w MCTD i składa się z polipeptydu zawierającego 437 reszt aminokwasowych, który wiąże się niekowalencyjnie z U1-RNA poprzez domenę wiążącą RNA obejmującą reszty 92-202. Ta domena wiążąca RNA zawiera dominujące epitopy rozpoznawane w MCTD.56

Mechanizmy patogenne przeciwciał anty-U1-RNP

Zaproponowano dwa główne mechanizmy patogenne, poprzez które przeciwciała anty-U1-RNP przyczyniają się do rozwoju MCTD:

  1. Bezpośrednie wiązanie z komórkami śródbłonka poprzez peptydy U1-RNP lub rozpoznawanie fragmentów nukleosomów RNP w pęcherzykach apoptotycznych komórek śródbłonka. Ten mechanizm może prowadzić do rozwoju fenotypu obejmującego choroby naczyniowe, takie jak objaw Raynauda, stwardnienie skóry i nadciśnienie płucne.7
  2. Tworzenie kompleksów immunologicznych, które mogą aktywować kaskadę dopełniacza i prowadzić do zapalenia tkanek i ich uszkodzenia, objawiającego się jako zapalenie mięśni, zapalenie stawów i śródmiąższowa choroba płuc.8

Przeciwciała anty-U1-RNP mogą stymulować zarówno komórki jednojądrzaste, jak i autoreaktywne limfocyty CD4+, prowadząc do zwiększonej produkcji interleukiny 1 (IL-1) i interleukiny 6 (IL-6), co przyczynia się do zapalenia autoimmunologicznego. Jednocześnie uszkodzenie tkanek jest podtrzymywane przez bezpośrednie działanie autoprzeciwciał na komórki śródbłonka.9

Rola apoptozy w patogenezie MCTD

Modyfikacje strukturalne zachodzące podczas apoptozy odgrywają kluczową rolę w rozwoju MCTD. Podczas procesu apoptozy, zmodyfikowane białko U1-70kDA jest eksponowane na powierzchni pęcherzyków apoptotycznych, co prowadzi do jego rozpoznania przez komórki prezentujące antygen, prezentacji limfocytom T i ostatecznie do stymulacji limfocytów B.10

Wykazano, że apoptotycznie zmodyfikowane białko 70-kD różni się antygenowo od nienaruszonych cząsteczek 70-kD, co może mieć istotne znaczenie w przełamywaniu tolerancji immunologicznej wobec autoantygenów. Badania wykazały, że autoprzeciwciała reagujące z apoptotycznym białkiem 70-kD są lepszymi markerami MCTD niż te przeciwko nienaruszonym cząsteczkom 70-kD.11

Co istotne, komponenta RNA unikalny dla U1-małej jądrowej rybonukleoproteiny, U1-RNA, jest jednym z najczęściej występujących RNA obecnych w apoptotycznych resztkach komórkowych i jest agonistą receptorów Toll-podobnych związanych z autoimmunizacją, w tym TLR7 i TLR3. Obserwacje te wspierają hipotezę, że rozpoznanie immunologiczne resztek apoptotycznych może odgrywać kluczową rolę w etiologii autoimmunizacji anty-RNP, jak w MCTD.12

Predyspozycje genetyczne do MCTD

Badania genetyczne dostarczyły dowodów, że MCTD jest odrębną jednostką chorobową w porównaniu z innymi chorobami tkanki łącznej. Związek genetyczny MCTD z fenotypami HLA-DR4 i DR2 wskazuje na zaangażowanie receptorów komórek T i cząsteczek HLA w generowaniu przeciwciał anty-U1-RNP.13

Nowsze badania wykazały silne powiązanie z HLA-DRB1*04:01 i HLA B*08 jako allelami ryzyka dla MCTD. Jest to genetycznie różne od SLE, które charakteryzuje się HLA-DR2 i HLA-DR3, twardziny związanej z HLA-DR5/11, HLA-DR3 i DR2 czy zapalenia wielomięśniowego związanego z HLA-DR3.1415

W norweskiej kohorcie zidentyfikowano HLA-B*08 i DRB1*04:01 jako allele ryzyka dla MCTD, podczas gdy DRB1*04:04, DRB1*13:01 i DRB1*13:02 miały działanie ochronne. Odkryto również nowe powiązanie między HLA-DRB1*03:01 a zwłóknieniem płuc w MCTD.16

Rola receptorów Toll-podobnych w patogenezie MCTD

Receptory Toll-podobne (TLR) odgrywają istotną rolę w patogenezie MCTD. Autoantygeny związane z MCTD są rozpoznawane przez endosomalne TLR, których aktywacja indukuje wyższą sekrecję interferonów typu I (IFN I), IFN-γ, regulację w górę genów indukowanych przez IFN (tzw. sygnatura interferonowa), a także wyższą produkcję specyficznych autoprzeciwciał.17

Kompleks immunologiczny U1-snRNP, który zawiera własną cząsteczkę RNA, może indukować odpowiedź immunologiczną poprzez zaangażowanie specyficznych autoreaktywnych endosomalnych receptorów Toll-podobnych (TLR). Badania wykazały, że U1-RNA może aktywować komórki poprzez TLR3, wykorzystując U1-RNA i linie komórkowe endometrium z mutacjami w genach TLR.18

Obecność dwuniciowego RNA w kompleksie U1 jest odpowiedzialna za aktywację odporności wrodzonej poprzez receptor Toll-podobny 3, aktywując również wrodzoną odporność. Anti-U1RNP wydaje się być zdolny do aktywacji niedojrzałych komórek dendrytycznych poprzez TLR7, indukując produkcję interferonu typu I (IFN-1), który z kolei może promować aktywację autoreaktywnych limfocytów T, z regulacją w dół limfocytów T regulatorowych i produkcją efektorowych limfocytów T, ostatecznie odpowiedzialnych za uszkodzenie tkanek.19

Rola interferonów w patogenezie MCTD

Interferony typu I (IFN-I) i interferon gamma (IFN-γ) odgrywają znaczącą rolę w patogenezie MCTD. Badania wykazały, że nadmierna aktywacja immunologiczna z udziałem TLR i IFN jest jednym z kluczowych mechanizmów patogennych tej choroby.20

Wykazano istotne powiązanie polimorfizmów genów IFN-A rs10757212, IFN-A rs3758236, IFN-G rs2069705 i IFN-G rs2069718 z występowaniem MCTD. Dodatkowo wariant genetyczny IFN-G w pozycji rs2069718 G/A może być związany z niektórymi objawami klinicznymi MCTD, takimi jak objaw Raynauda, nadżerkowe zapalenie stawów, obrzęk rąk i palców oraz sklerodaktylia.21

Interferon typu I aktywuje autoreaktywne limfocyty T, prowadząc do produkcji autoprzeciwciał. Aktywność typu I interferonu wydaje się być związana z pozytywnością pewnych autoprzeciwciał, co stanowi dodatkowy dowód na patogenną rolę interferonu typu I w chorobach autoimmunologicznych.2223

Rola limfocytów T i B w patogenezie

Zarówno limfocyty T, jak i B odgrywają kluczową rolę w patogenezie MCTD. W MCTD dochodzi do złożonej interakcji między układem odpornościowym wrodzonym i adaptacyjnym, która kulminuje w chorobie autoimmunologicznej.24

Limfocyty T reaktywne wobec RNP zostały zidentyfikowane we krwi obwodowej pacjentów z MCTD. Zarówno przeciwciała anty-RNP, jak i anty-U1-RNA znalezione w surowicy pacjentów przeszły w większości przypadków przełączanie izotypów do podtypów immunoglobuliny G (IgG). W miejscach uszkodzenia tkanek w wynikach badań autopsyjnych i bioptatów od pacjentów obserwuje się również gęste nacieki limfocytarne z licznymi limfocytami T.25

Badania wykazały również, że ludzkie limfocyty T reaktywne wobec RNP mogą in vitro wspomagać produkcję autoprzeciwciał anty-RNP przez limfocyty B, co świadczy o współpracy komórek T i B w patogenezie MCTD.26

Zmiany naczyniowe w MCTD

Zmiany naczyniowe prowadzą do niektórych z najcięższych manifestacji klinicznych u pacjentów z MCTD. Podstawowa patogeneza w MCTD obejmuje waskulopatię prowadzącą do niedokrwienia tkanek, procesy immunologiczne i zapalne oraz zwłóknienie spowodowane nadmierną syntezą kolagenu i innych białek macierzy.27

U dorosłych pacjentów z MCTD stwierdzono niekontrolowaną nadekspresję czynników angiogennych i angiostatycznych (czynnik wzrostu śródbłonka naczyniowego [VEGF] i endostatyna). Poziomy VEGF były wyższe u pacjentów z MCTD z nadciśnieniem płucnym i zapaleniem mięśni, potencjalnie charakteryzując pacjentów z cięższym przebiegiem choroby.28

Badania z wykorzystaniem angiografii optycznej koherentnej tomografii wykazały nieprawidłowości naczyniowe oczne u pacjentów z MCTD, zmniejszoną gęstość naczyń siatkówki i niższy przepływ w naczyniach włosowatych naczyniówki. Wyniki te podkreślają ważną rolę zmian mikronaczyniowych w MCTD.29

Metylacja DNA w patogenezie MCTD

Metylacja DNA jest najlepiej poznaną modyfikacją epigenetyczną, której rolą jest regulacja ekspresji genów. Badania wykazały istotne różnice w globalnej metylacji DNA między pacjentami z MCTD a pacjentami z innymi chorobami tkanki łącznej.30

Analizy wykazały statystycznie istotną różnicę globalnej metylacji między SLE a MCTD (p < 0,001), SLE a zdrową kontrolą (p = 0,008), twardziną a MCTD (p ≤ 0,001) oraz twardziną a zdrową kontrolą (p < 0,001), ale nie między MCTD a zdrową kontrolą (p = 0,09) ani twardziną a SLE (p = 0,08).31

Badania dostarczyły dowodów na globalną hipometylację DNA u pacjentów z MCTD. Chociaż poziom globalnej metylacji DNA może nie być dobrym markerem diagnostycznym do odróżnienia MCTD od innych chorób tkanki łącznej, badania wykazały duży potencjał poziomu globalnej metylacji DNA krwi pełnej do rozróżniania pacjentów z MCTD i innymi chorobami tkanki łącznej.32

Rola mikroRNA w patogenezie MCTD

MikroRNA (miRNA) są ważnymi regulatorami układu odpornościowego i odpowiedzi immunologicznej. Specyficzne miRNA modulują prezentację antygenów, selekcję klonalną, funkcję limfocytów Treg, produkcję cytokin, rekrutację komórek zapalnych zależnych od chemokin, produkcję przeciwciał i nieimmunologiczne mechanizmy uszkodzenia tkanek.33

Badania wykazały możliwe znaczenie miR-146a i miR-143/145 w podatności i obrazie klinicznym MCTD. Analiza dystrybucji wykazała, że spośród wszystkich badanych mikroRNA tylko allel C miR-146a rs2910164 może skutkować genetyczną predyspozycją do MCTD. Genotyp miR-146a rs2910164 CC był znacząco częstszy wśród pacjentów z MCTD z twardziną.34

Analiza wykazała również, że wariant genetyczny miR-143 rs353298 A/G był związany z występowaniem zapalenia osierdzia/opłucnej i twardziny. Te odkrycia sugerują, że polimorfizmy genów miRNA mogą odgrywać rolę w podatności na MCTD i w jej manifestacjach klinicznych.35

Model zwierzęcy MCTD

Opracowano mysi model MCTD, który pomoże w zaawansowaniu badań przedklinicznych i translacyjnych w tej chorobie. Model ten został stworzony z autoantygenem U1 small nuclear RNP i dostarcza cennych informacji na temat mechanizmów patogenetycznych MCTD.3637

Badania na tym modelu zwierzęcym wykazały, że limfocyty T CD4+ są ukierunkowane na epitopy znajdujące się w domenie wiążącej RNA autoantigenu U1-70-kDa small nuclear ribonucleoprotein i mają ograniczoną różnorodność TCR w transgenicznym mysim modelu MCTD z HLA-DR4.38

Dalsze badania na tym modelu wykazały, że ukierunkowanie tkanki przez autoimmunizację anty-RNP wiąże się z efektami limfocytów T i mieloidalnych komórek dendrytycznych, co potwierdza złożone interakcje komórkowe w patogenezie MCTD.39

Implikacje kliniczne patogenezy dla manifestacji choroby

Zrozumienie patogenezy MCTD ma bezpośrednie implikacje dla manifestacji klinicznych choroby i jej leczenia. Dwie główne komplikacje – nadciśnienie płucne i śródmiąższowa choroba płuc – są najczęstszymi przyczynami zgonów w MCTD.40

Badania wykazały, że pacjenci z MCTD-twardziną układową mają znacząco lepsze przeżycie w porównaniu z pacjentami z samą twardziną układową (p=0,011). Obecność przeciwciał anty-RNP wiąże się z lepszym przeżyciem niż przeciwciała anty-Scl-70 i anty-RNA polimerazy 3.4142

Pomiar aktywności choroby przy użyciu SLEDAI-2 K i EUSTAR-AI wykazał znacząco lepszą odpowiedź na leczenie objawów podobnych do SLE niż objawów podobnych do twardziny układowej, co jest zgodne z wcześniejszymi danymi.43

Lepsze zrozumienie mechanizmów patogenetycznych MCTD może prowadzić do opracowania nowych, ukierunkowanych terapii, szczególnie przeciw interferonom typu I, które wykazały obiecujące wyniki w badaniach klinicznych u pacjentów z wysoką sygnaturą interferonową.44

Wnioski i przyszłe kierunki badań

Mieszana choroba tkanki łącznej jest złożoną chorobą autoimmunologiczną charakteryzującą się wysokim mianem przeciwciał anty-U1-RNP i nakładającymi się objawami różnych chorób tkanki łącznej. Autoimmunizacja wobec specyficznych składników splicesomu jest immunologiczną charakterystyką MCTD.45

Dokładna patogeneza MCTD nadal nie jest w pełni wyjaśniona, ale obecne badania wspierają model, w którym złożone interakcje między czynnikami genetycznymi, środowiskowymi i immunologicznymi prowadzą do rozwoju choroby. Kluczowe mechanizmy obejmują:

  • Autoimmunizację przeciwko U1-RNP, szczególnie przeciwko podjednostce 70 kDa46
  • Modyfikacje apoptotyczne autoantygenu47
  • Aktywację receptorów Toll-podobnych przez komponenty U1-RNA48
  • Produkcję interferonów typu I i IFN-γ49
  • Współpracę autoreaktywnych limfocytów T i B50
  • Waskulopatię i zmiany naczyniowe51

Przyszłe badania powinny koncentrować się na lepszym zrozumieniu czynników wyzwalających autoimmunizację anty-U1-RNP, roli określonych genów HLA w predyspozycji do choroby oraz mechanizmów prowadzących do uszkodzenia tkanek. Rozwój ukierunkowanych terapii, szczególnie tych hamujących szlak interferonu typu I, może oferować nowe możliwości leczenia dla pacjentów z MCTD.52

Lepsze zrozumienie patogenezy MCTD może również pomóc w odpowiedzi na pytanie, czy MCTD jest oddzielną jednostką chorobową, czy też wariantem innych chorób tkanki łącznej, co ma istotne implikacje dla diagnostyki i leczenia.53

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  1. 10.04.2026
  2. www.leksykon.com.pl

Materiały źródłowe

  • #1 Immune pathogenesis of Mixed Connective Tissue Disease: a short analytical review – PubMed
    https://pubmed.ncbi.nlm.nih.gov/18439877/
    Mixed Connective Tissue Disease (MCTD) was first described 35 years ago by Gordon C. Sharp and his colleagues. […] Studies on immune pathogenesis have made substantial progress in advancing our understanding of MCTD. In MCTD, there is a complex interaction of the innate and adaptive immune system that culminates in autoimmune disease. Antigenic structural modification occurring during apoptosis or other modifications of self antigens leads to an autoantigen driven immune process with innate immune activation, immunoglobulin G autoantibody production directed against select components of the spliceosome, B lymphocyte activation, and CD4 and CD8 T lymphocyte participation.
  • #2 Mixed Connective-Tissue Disease (MCTD): Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/335815-overview
    Mixed connective-tissue disease (MCTD) is a rare systemic autoimmune disease with overlapping features of at least two connective tissue diseases, including systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis, dermatomyositis, and rheumatoid arthritis. […] Pathophysiologic abnormalities that are believed to play a role in MCTD include the following: B-lymphocyte hyperactivity, resulting in high levels of antiU1-RNP and antiU1-70 kd autoantibodies; T-lymphocyte activation, with antiU1-70 kd reactive T lymphocytes circulating in the peripheral blood; apoptotic modification of the U1-70 kd antigen; immune response against apoptotically modified self-antigens; genetic association with major histocompatibility genes human leukocyte antigen (HLA)DRB1*04/*15; vascular endothelial pathology, including features of hyperproliferation and increased endothelial apoptosis; lymphocytic and plasmacytic infiltration of tissues; activation of Toll-like receptors in a pattern that may differ from that of classic SLE; a strong Type I Interferon activation signature in circulating cells.
  • #3 Mixed Connective Tissue Disease | Treatment & Management | Point of Care
    https://www.statpearls.com/point-of-care/25207
    Given the anti-U1-RNP antibody is the hallmark of MCTD, it is believed that the anti-U1-RNP antibody and its antigen play a role in the pathogenesis of MCTD. The U1-RNP complex is an intranuclear protein that converts pre-messenger RNA to mature RNA. This complex comprises 3 specific proteins A, C, and 70 kDa to which anti-U1 RNP antibodies bind. The 70 kDa antigen is the main target of the anti-RNP antibody in MCTD. The genetic association of MCTD with HLA-DR4 and DR2 phenotypes indicates the involvement of T-cell receptors and HLA molecules in the generation of anti-U1-RNP. […] Two main mechanisms have been proposed for the pathogenic role of anti-U1-RNP antibodies. The first mechanism involves direct binding to endothelial cells through U1-RNP peptides or recognition of nucleosome RNP fragments in endothelial cell apoptotic blebs. This mechanism may lead to the phenotype involving vascular diseases such as Raynaud phenomenon, skin sclerosis, and pulmonary hypertension. The second possible pathogenic mechanism is through immune complex formation, which can activate the complement cascade and lead to tissue inflammation and damage, such as myositis, arthritis, and interstitial lung disease.
  • #4 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    MCTD is characterized immunologically by the presence of autoantibodies and T cells reactive with U1-RNP and polypeptides of the spliceosome complex, including their associated uridine-rich (U) small nuclear ribonucleic acids (RNAs). […] A number of immunological factors have been associated with MCTD and may contribute to disease pathogenesis. […] The 70-kD peptide of the U1-RNP antigen appears to be a dominant autoantigen in MCTD and consists of a 437 residue polypeptide, which noncovalently associates with U1-RNA through an RNA binding domain on the polypeptide spanning residues 92-202. […] There are a variety of potential and proven structural modifications, which occur to the U1 70-kD polypeptide and RNP, any of which might influence antigenicity of the RNP complex. […] The apoptotically modified 70-kD has been shown to be antigenically distinct from intact 70-kD, which may have clinical implications in breaking immune tolerance to the autoantigen.
  • #5 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    MCTD is characterized immunologically by the presence of autoantibodies and T cells reactive with U1-RNP and polypeptides of the spliceosome complex, including their associated uridine-rich (U) small nuclear ribonucleic acids (RNAs). […] A number of immunological factors have been associated with MCTD and may contribute to disease pathogenesis. […] The 70-kD peptide of the U1-RNP antigen appears to be a dominant autoantigen in MCTD and consists of a 437 residue polypeptide, which noncovalently associates with U1-RNA through an RNA binding domain on the polypeptide spanning residues 92-202. […] There are a variety of potential and proven structural modifications, which occur to the U1 70-kD polypeptide and RNP, any of which might influence antigenicity of the RNP complex. […] The apoptotically modified 70-kD has been shown to be antigenically distinct from intact 70-kD, which may have clinical implications in breaking immune tolerance to the autoantigen.
  • #6 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    One study reported that autoantibodies reactive with apoptotic 70-kD are superior markers to those against intact 70-kD for MCTD. […] Various independent observations over the years have led to the conclusion that the innate and adaptive immune systems play a central role in the development of many systemic autoimmune diseases, including MCTD. […] As noted previously, the dominant epitopes recognized in MCTD reside within the RNA binding domains of the peptide. […] These observations coincided with the discovery of a series of pathogen-associated pattern recognition receptors, including the Toll-like receptors (TLRs), especially those that recognize double-stranded RNA or single-stranded RNA, and normally play a vital role in host defense through their recognition of bacterial and viral cell products.
  • #7 Mixed Connective Tissue Disease | Treatment & Management | Point of Care
    https://www.statpearls.com/point-of-care/25207
    Given the anti-U1-RNP antibody is the hallmark of MCTD, it is believed that the anti-U1-RNP antibody and its antigen play a role in the pathogenesis of MCTD. The U1-RNP complex is an intranuclear protein that converts pre-messenger RNA to mature RNA. This complex comprises 3 specific proteins A, C, and 70 kDa to which anti-U1 RNP antibodies bind. The 70 kDa antigen is the main target of the anti-RNP antibody in MCTD. The genetic association of MCTD with HLA-DR4 and DR2 phenotypes indicates the involvement of T-cell receptors and HLA molecules in the generation of anti-U1-RNP. […] Two main mechanisms have been proposed for the pathogenic role of anti-U1-RNP antibodies. The first mechanism involves direct binding to endothelial cells through U1-RNP peptides or recognition of nucleosome RNP fragments in endothelial cell apoptotic blebs. This mechanism may lead to the phenotype involving vascular diseases such as Raynaud phenomenon, skin sclerosis, and pulmonary hypertension. The second possible pathogenic mechanism is through immune complex formation, which can activate the complement cascade and lead to tissue inflammation and damage, such as myositis, arthritis, and interstitial lung disease.
  • #8 Mixed Connective Tissue Disease | Treatment & Management | Point of Care
    https://www.statpearls.com/point-of-care/25207
    Given the anti-U1-RNP antibody is the hallmark of MCTD, it is believed that the anti-U1-RNP antibody and its antigen play a role in the pathogenesis of MCTD. The U1-RNP complex is an intranuclear protein that converts pre-messenger RNA to mature RNA. This complex comprises 3 specific proteins A, C, and 70 kDa to which anti-U1 RNP antibodies bind. The 70 kDa antigen is the main target of the anti-RNP antibody in MCTD. The genetic association of MCTD with HLA-DR4 and DR2 phenotypes indicates the involvement of T-cell receptors and HLA molecules in the generation of anti-U1-RNP. […] Two main mechanisms have been proposed for the pathogenic role of anti-U1-RNP antibodies. The first mechanism involves direct binding to endothelial cells through U1-RNP peptides or recognition of nucleosome RNP fragments in endothelial cell apoptotic blebs. This mechanism may lead to the phenotype involving vascular diseases such as Raynaud phenomenon, skin sclerosis, and pulmonary hypertension. The second possible pathogenic mechanism is through immune complex formation, which can activate the complement cascade and lead to tissue inflammation and damage, such as myositis, arthritis, and interstitial lung disease.
  • #9 Towards early diagnosis of mixed connective tissue disease | ITT
    https://www.dovepress.com/towards-early-diagnosis-of-mixed-connective-tissue-disease-updated-per-peer-reviewed-fulltext-article-ITT
    Anti-U1-RNP can stimulate both mononuclear cells and autoreactive CD4+ cells, with an increased production of Interleukin (IL) 1 and IL6 (leading to autoimmune inflammation), but tissue injury is also sustained due to the direct action of the autoantibody on endothelial cells. […] This mechanism could explain the vascular involvement seen in MCTD, in particular Pulmonary Artery Hypertension (PAH). […] The presence of double stranded RNA in the U1 complex is responsible for the activation of innate immunity through Toll-like Receptor 3, activating also the innate immunity. […] Anti-U1RNP also seems to be able to activate immature dendritic cells via TLR7, inducing the production of Type I Interferon (IFN-1), in turn able to promote the activation of autoreactive T cells, with a down-regulation of regulatory T cells and the production of effector T cells, ultimately responsible of the tissue injury. […] IFN-1 also activates autoreactive T cells, leading to the production of autoantibodies.
  • #10 Towards early diagnosis of mixed connective tissue disease | ITT
    https://www.dovepress.com/towards-early-diagnosis-of-mixed-connective-tissue-disease-updated-per-peer-reviewed-fulltext-article-ITT
    Mixed Connective Tissue Disease (MCTD) is an autoimmune disease first described by Sharp et al in 1972, characterized by the presence of anti-Ribonucleoprotein antibodies directed against the U1 complex (anti-U1RNP). […] The pathophysiology of this condition is also largely unknown, but it clearly seems to be multifactorial. A genetic association with the development of MCTD was found in patients with HLA-DR4, but not with HLA-DR3 and -DR5 (which are strongly associated with SLE and SSc respectively). […] The hallmark of the disease is represented by anti-U1RNP (or anti-nRNP), an autoantibody directed against the 70kDa subunit of the U1 RNP complex, an intracellular protein involved in mRNA maturation. […] It is possible that during the process of apoptosis, a modified U1 70kDA protein is exposed on the surface of the apoptotic blebs, which is then recognized by antigen-presenting cells, presented to T cells, leading ultimately to B cell stimulation.
  • #11 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    One study reported that autoantibodies reactive with apoptotic 70-kD are superior markers to those against intact 70-kD for MCTD. […] Various independent observations over the years have led to the conclusion that the innate and adaptive immune systems play a central role in the development of many systemic autoimmune diseases, including MCTD. […] As noted previously, the dominant epitopes recognized in MCTD reside within the RNA binding domains of the peptide. […] These observations coincided with the discovery of a series of pathogen-associated pattern recognition receptors, including the Toll-like receptors (TLRs), especially those that recognize double-stranded RNA or single-stranded RNA, and normally play a vital role in host defense through their recognition of bacterial and viral cell products.
  • #12 Mixed Connective-Tissue Disease (MCTD): Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/335815-overview
    The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP is a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within 1 year of anti-RNP antibody induction. The loss of T-lymphocyte and B-lymphocyte tolerance, due to cryptic self-antigens, abnormalities of apoptosis, or molecular mimicry by infectious agents, and driven by U1-RNA induced innate immune responses and other danger signal sensors induced by end-organ injury, are proposed current theories of pathogenesis. […] It is notable that the RNA component unique to the U1-small nuclear ribonucleoprotein, U1-RNA, is among the most prevalent RNAs present in cellular apoptotic debris, and that U1-RNA is an agonist for autoimmunity-associated endosomal Toll-like receptors, including TLR7 and TLR3. These observations promote the hypothesis that immune recognition of apoptotic debris may play a key role in the etiology of anti-RNP autoimmunity, as in MCTD.
  • #13 Mixed Connective Tissue Disease | Treatment & Management | Point of Care
    https://www.statpearls.com/point-of-care/25207
    Given the anti-U1-RNP antibody is the hallmark of MCTD, it is believed that the anti-U1-RNP antibody and its antigen play a role in the pathogenesis of MCTD. The U1-RNP complex is an intranuclear protein that converts pre-messenger RNA to mature RNA. This complex comprises 3 specific proteins A, C, and 70 kDa to which anti-U1 RNP antibodies bind. The 70 kDa antigen is the main target of the anti-RNP antibody in MCTD. The genetic association of MCTD with HLA-DR4 and DR2 phenotypes indicates the involvement of T-cell receptors and HLA molecules in the generation of anti-U1-RNP. […] Two main mechanisms have been proposed for the pathogenic role of anti-U1-RNP antibodies. The first mechanism involves direct binding to endothelial cells through U1-RNP peptides or recognition of nucleosome RNP fragments in endothelial cell apoptotic blebs. This mechanism may lead to the phenotype involving vascular diseases such as Raynaud phenomenon, skin sclerosis, and pulmonary hypertension. The second possible pathogenic mechanism is through immune complex formation, which can activate the complement cascade and lead to tissue inflammation and damage, such as myositis, arthritis, and interstitial lung disease.
  • #14 Mixed connective tissue disease | Radiology Key
    https://radiologykey.com/mixed-connective-tissue-disease-2/
    Mixed connective tissue disease (MCTD) was first described in Sharp et al. (1972). It is characterized by an overlap of signs and symptoms of systemic lupus erythematosus (SLE), scleroderma and polymyositis-dermatomyositis, with antibodies against the U1-ribonucleoprotein (U1-RNP). […] The aetiology of mixed connective tissue disease is unknown, and the development of the disease is probably linked to interaction of genetic and environmental factors. The major histocompatibility complex (HLA) genes are implicated in the genetic predisposition of the disease. Classically, the HLA-DR4 and HLA-DRw53 genes have been related to MCTD and anti-U1-RNP-70kD antibodies. Recent studies show a strong association with HLA-DRB1*04:01 and HLA B*08. Therefore, MCTD is genetically different from SLE, which is characterized by HLA-DR2 and HLA-DR3, HLA-DRB1, HLA-DRB1*0301 and HLA-DRB1*1501; scleroderma associated with HLA-DR5/11, HLA-DR3 and DR2 or HLA-DQA1*0501; or polymyositis which is associated with HLA-DR3, HLA-B*0801 and DRB1*0301. Thus, MCTD is a distinct entity within autoimmune rheumatic diseases and path mechanism as described in Fig. 2.2.1.
  • #15 Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Children | Musculoskeletal Key
    https://musculoskeletalkey.com/undifferentiated-connective-tissue-disease-mixed-connective-tissue-disease-and-overlap-syndromes-in-children/
    The exact etiology of MCTD remains unknown. Immunological, genetic, and environmental factors play a role in the pathogenesis. Autoimmunity seems to be the hallmark with both T- and B-cell involvement. The 70 kD peptide of the U1 RNP antigen is the dominant antigen against which autoantibodies are produced. […] Genetic associations with HLA-DR4 and DR2 have been recognized though familial occurrence is rare. In a Norwegian cohort, HLA-B*08 and DRB1*04:01 were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01, and DRB1*13:02 were protective. A novel association between HLA-DRB1*03:01 and pulmonary fibrosis in MCTD was also identified. This study reinforced the fact that HLA profile of patients with MCTD was distinct compared to other CTDs, and MCTD was a different entity than other rheumatological diseases. […] Unlike SLE, sun exposure is not a precipitating factor. Drug-induced MCTD is a rare occurrence but may be occasionally seen with anti-tumor necrosis factor (TNF) therapy. Vinyl chloride and silica are the only environmental agents that have been associated with MCTD.
  • #16 Undifferentiated Connective Tissue Disease, Mixed Connective Tissue Disease, and Overlap Syndromes in Children | Musculoskeletal Key
    https://musculoskeletalkey.com/undifferentiated-connective-tissue-disease-mixed-connective-tissue-disease-and-overlap-syndromes-in-children/
    The exact etiology of MCTD remains unknown. Immunological, genetic, and environmental factors play a role in the pathogenesis. Autoimmunity seems to be the hallmark with both T- and B-cell involvement. The 70 kD peptide of the U1 RNP antigen is the dominant antigen against which autoantibodies are produced. […] Genetic associations with HLA-DR4 and DR2 have been recognized though familial occurrence is rare. In a Norwegian cohort, HLA-B*08 and DRB1*04:01 were identified as risk alleles for MCTD, while DRB1*04:04, DRB1*13:01, and DRB1*13:02 were protective. A novel association between HLA-DRB1*03:01 and pulmonary fibrosis in MCTD was also identified. This study reinforced the fact that HLA profile of patients with MCTD was distinct compared to other CTDs, and MCTD was a different entity than other rheumatological diseases. […] Unlike SLE, sun exposure is not a precipitating factor. Drug-induced MCTD is a rare occurrence but may be occasionally seen with anti-tumor necrosis factor (TNF) therapy. Vinyl chloride and silica are the only environmental agents that have been associated with MCTD.
  • #17 Interferons (IFN-A/-B/-G) Genetic Variants in Patients with Mixed Connective Tissue Disease (MCTD)
    https://www.mdpi.com/2077-0383/8/12/2046
    Mixed connective tissue disease (MCTD) is a rare complex autoimmune disease in which autoantigens are recognized by endosomal TLRs. Their activation induces a higher secretion of the type I interferons, IFN-γ and the up-regulation of the INF-inducible genes. […] The presence of high-titer of anti-U1-snRNP antibodies (autoantibodies against the U1-small nuclear ribonucleoprotein antigen) in serum is an important hallmark of MCTD, which is a part of the diagnostic criteria for MCTD. […] The U1-snRNP immune complex, which contains its own RNA molecule, might induce an immune response through the involvement of specific autoreactive endosomal Toll-like receptors (TLRs). […] MCTD-associated autoantigens are recognized by endosomal TLRs, where activation induces a higher secretion of the type I interferons (IFN I), IFN-γ, up-regulation of the IFN-inducible genes (called IFN signature), as well as higher production of the specific autoantibodies.
  • #18 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    These findings led to a series of studies examining TLRs in autoimmunity. […] Studies have shown that U1-RNA can activate cells of a TLR3 using U1-RNA and TLR-deficient mutant endometrial cell lines. […] Autoantibodies are widely recognized as a hallmark of many of the rheumatic diseases, including MCTD. […] Two studies have supported a role for anti-RNP antibodies in the pathogenesis of MCTD by providing linkage between the emergence of antibodies and clinical disease. […] B cells can function in several other key immunological pathways beyond antibody production; these include functioning as antigen-presenting cells, secreting pathological cytokines, and mediating tissue injury through a variety of antibody-directed mechanisms. […] T cells appear to have a central role in the pathogenesis of MCTD.
  • #19 Towards early diagnosis of mixed connective tissue disease | ITT
    https://www.dovepress.com/towards-early-diagnosis-of-mixed-connective-tissue-disease-updated-per-peer-reviewed-fulltext-article-ITT
    Anti-U1-RNP can stimulate both mononuclear cells and autoreactive CD4+ cells, with an increased production of Interleukin (IL) 1 and IL6 (leading to autoimmune inflammation), but tissue injury is also sustained due to the direct action of the autoantibody on endothelial cells. […] This mechanism could explain the vascular involvement seen in MCTD, in particular Pulmonary Artery Hypertension (PAH). […] The presence of double stranded RNA in the U1 complex is responsible for the activation of innate immunity through Toll-like Receptor 3, activating also the innate immunity. […] Anti-U1RNP also seems to be able to activate immature dendritic cells via TLR7, inducing the production of Type I Interferon (IFN-1), in turn able to promote the activation of autoreactive T cells, with a down-regulation of regulatory T cells and the production of effector T cells, ultimately responsible of the tissue injury. […] IFN-1 also activates autoreactive T cells, leading to the production of autoantibodies.
  • #20 Interferons (IFN-A/-B/-G) Genetic Variants in Patients with Mixed Connective Tissue Disease (MCTD)
    https://www.mdpi.com/2077-0383/8/12/2046
    Although the detailed etiopathogenesis of systemic CTDs is not established, the growing volume of published studies has confirmed that excessive immunological activation with TLRs and IFNs is very important/one of the crucial pathogenic mechanisms of these diseases. […] Our results indicate that IFN-G genetic variants may be potential genetic biomarkers for MCTD susceptibility and severity. […] The present study demonstrates, for the first time, the association between IFN-A, IFN-B, and IFN-G genetic variants and MCTD risk, phenotype, and serological profile. […] Our results showed a significant association of the IFN-A rs10757212, IFN-A rs3758236, IFN-G rs2069705, and IFN-G rs2069718 gene polymorphisms with the occurrence of MCTD. […] Our results also demonstrated that the IFN-G genetic variant at position rs2069718 G/A might be associated with some clinical symptoms of MCTD, such as Raynaud’s Phenomenon, erosive arthritis, swollen hands and fingers, and sclerodactyly.
  • #21 Interferons (IFN-A/-B/-G) Genetic Variants in Patients with Mixed Connective Tissue Disease (MCTD)
    https://www.mdpi.com/2077-0383/8/12/2046
    Although the detailed etiopathogenesis of systemic CTDs is not established, the growing volume of published studies has confirmed that excessive immunological activation with TLRs and IFNs is very important/one of the crucial pathogenic mechanisms of these diseases. […] Our results indicate that IFN-G genetic variants may be potential genetic biomarkers for MCTD susceptibility and severity. […] The present study demonstrates, for the first time, the association between IFN-A, IFN-B, and IFN-G genetic variants and MCTD risk, phenotype, and serological profile. […] Our results showed a significant association of the IFN-A rs10757212, IFN-A rs3758236, IFN-G rs2069705, and IFN-G rs2069718 gene polymorphisms with the occurrence of MCTD. […] Our results also demonstrated that the IFN-G genetic variant at position rs2069718 G/A might be associated with some clinical symptoms of MCTD, such as Raynaud’s Phenomenon, erosive arthritis, swollen hands and fingers, and sclerodactyly.
  • #22 Towards early diagnosis of mixed connective tissue disease | ITT
    https://www.dovepress.com/towards-early-diagnosis-of-mixed-connective-tissue-disease-updated-per-peer-reviewed-fulltext-article-ITT
    Anti-U1-RNP can stimulate both mononuclear cells and autoreactive CD4+ cells, with an increased production of Interleukin (IL) 1 and IL6 (leading to autoimmune inflammation), but tissue injury is also sustained due to the direct action of the autoantibody on endothelial cells. […] This mechanism could explain the vascular involvement seen in MCTD, in particular Pulmonary Artery Hypertension (PAH). […] The presence of double stranded RNA in the U1 complex is responsible for the activation of innate immunity through Toll-like Receptor 3, activating also the innate immunity. […] Anti-U1RNP also seems to be able to activate immature dendritic cells via TLR7, inducing the production of Type I Interferon (IFN-1), in turn able to promote the activation of autoreactive T cells, with a down-regulation of regulatory T cells and the production of effector T cells, ultimately responsible of the tissue injury. […] IFN-1 also activates autoreactive T cells, leading to the production of autoantibodies.
  • #23 The Type I Interferon Pathway’s Influence in Connective Tissue Disease – The Rheumatologist
    https://www.the-rheumatologist.org/article/the-type-i-interferon-pathways-influence-in-connective-tissue-disease/
    In contrast, several studies have demonstrated that type I interferon correlates with muscle enzyme levels in inflammatory myositis, suggesting that elevated type I interferon might play more of a role in flare activation in that condition. […] High type I interferon activity seems to be associated with positivity of certain autoantibodies as well. […] Another critical line of evidence pointing to the pathogenic role of type I interferon emerged in the first decade of the 21st century. […] When you look at the list of genes, definitely in lupus but in some other diseases too, many type I interferon pathway genes were associated with disease. […] Are interferons more important early on, when the immune system is starting to break tolerance? […] Other lines of evidence also support the idea of the pathogenic role of type I interferon.
  • #24 Immune pathogenesis of Mixed Connective Tissue Disease: a short analytical review – PubMed
    https://pubmed.ncbi.nlm.nih.gov/18439877/
    Mixed Connective Tissue Disease (MCTD) was first described 35 years ago by Gordon C. Sharp and his colleagues. […] Studies on immune pathogenesis have made substantial progress in advancing our understanding of MCTD. In MCTD, there is a complex interaction of the innate and adaptive immune system that culminates in autoimmune disease. Antigenic structural modification occurring during apoptosis or other modifications of self antigens leads to an autoantigen driven immune process with innate immune activation, immunoglobulin G autoantibody production directed against select components of the spliceosome, B lymphocyte activation, and CD4 and CD8 T lymphocyte participation.
  • #25 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    RNP-reactive CD4 + T cells have been identified from peripheral blood of MCTD patients. […] Both anti-RNP and anti-U1-RNA antibodies found in patients sera have, in most instances, undergone isotope switching to immunoglobulin G (IgG) subtypes. […] Also, there is dense lymphocyte infiltration, with many T cells found in the sites of tissue injury at autopsy and in biopsy specimens from patients. […] Findings have also shown that human RNP reactive T cells can provide B-cell help in vitro to anti-RNP autoantibody production. […] Vascular alterations result in some of the most severe clinical manifestations in patients with MCTD. […] Uncontrolled overexpression of angiogenic and angiostatic factors (vascular endothelial growth factor [VEGF] and endostatin) were found in adult MCTD patients.
  • #26 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    RNP-reactive CD4 + T cells have been identified from peripheral blood of MCTD patients. […] Both anti-RNP and anti-U1-RNA antibodies found in patients sera have, in most instances, undergone isotope switching to immunoglobulin G (IgG) subtypes. […] Also, there is dense lymphocyte infiltration, with many T cells found in the sites of tissue injury at autopsy and in biopsy specimens from patients. […] Findings have also shown that human RNP reactive T cells can provide B-cell help in vitro to anti-RNP autoantibody production. […] Vascular alterations result in some of the most severe clinical manifestations in patients with MCTD. […] Uncontrolled overexpression of angiogenic and angiostatic factors (vascular endothelial growth factor [VEGF] and endostatin) were found in adult MCTD patients.
  • #27 Mixed connective tissue disease pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Mixed_connective_tissue_disease_pathophysiology
    MCTD is a systemic autoimmune disease that is characterized by overlapping symptoms of two or more systemic autoimmune diseases (SLE, RA, DM, polymyositis, and scleroderma) and the presence of antibodies against U1snRNP. […] Primary pathogenesis in MCTD include vasculopathy leading to tissue ischemia, immunological and inflammatory processes and fibrosis caused by excessive synthesis of collagen and other proteins of matrix. […] MCTD is characterized by clinical symptoms seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis (DM), polymyositis, and scleroderma. […] Primary pathogenesis in MCTD include: vasculopathy leading to tissue ischemia, autoimmunity causes immunological and inflammatory, fibrosis caused by excessive synthesis of collagen and other proteins of matrix. […] In MCTD, U1-snRNP components play an important role for triggering immune responses. […] Two complications of pulmonary hypertension and interstitial lung disease are the most frequent causes of death.
  • #28 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    RNP-reactive CD4 + T cells have been identified from peripheral blood of MCTD patients. […] Both anti-RNP and anti-U1-RNA antibodies found in patients sera have, in most instances, undergone isotope switching to immunoglobulin G (IgG) subtypes. […] Also, there is dense lymphocyte infiltration, with many T cells found in the sites of tissue injury at autopsy and in biopsy specimens from patients. […] Findings have also shown that human RNP reactive T cells can provide B-cell help in vitro to anti-RNP autoantibody production. […] Vascular alterations result in some of the most severe clinical manifestations in patients with MCTD. […] Uncontrolled overexpression of angiogenic and angiostatic factors (vascular endothelial growth factor [VEGF] and endostatin) were found in adult MCTD patients.
  • #29 POS0880 OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH MIXED CONNECTIVE TISSUE DISEASE | Annals of the Rheumatic Diseases
    https://ard.bmj.com/content/83/Suppl_1/651.2
    The mechanism of vasculopathy associated with MCTD remains largely unknown. […] Our research indicates ocular vascular abnormalities in patient with MCTD, decreased retinal vessel density and lower choricapillaries flow. The results show the important role of OCTA in diagnosis and monitoring microvascular changes in MCTD patients.
  • #30 Mixed Connective Tissue Disease as Different Entity: Global Methylation Aspect
    https://www.mdpi.com/1422-0067/24/20/15495
    Mixed connective tissue disease (MCTD) is a very rare disorder that belongs in the rare and clinically multifactorial groups of diseases. The pathogenesis of MCTD is still unclear. The best understood epigenetic alteration is DNA methylation whose role is to regulate gene expression. […] The aim of this study was to define the global DNA methylation changes between MCTD and other ACTDs patients in whole blood samples. […] The present analysis revealed a statistically significant difference of global methylation between SLE and MCTD (p < 0.001), SLE and HC (p = 0.008), SSc and MCTD (p ≤ 0.001), and SSc and HC (p < 0.001), but neither between MCTD and HC (p = 0.09) nor SSc and SLE (p = 0.08). [...] Our study showed that patients with limited SSc had a significantly higher global methylation level when compared to diffuse SSc.
  • #31 Mixed Connective Tissue Disease as Different Entity: Global Methylation Aspect
    https://www.mdpi.com/1422-0067/24/20/15495
    Mixed connective tissue disease (MCTD) is a very rare disorder that belongs in the rare and clinically multifactorial groups of diseases. The pathogenesis of MCTD is still unclear. The best understood epigenetic alteration is DNA methylation whose role is to regulate gene expression. […] The aim of this study was to define the global DNA methylation changes between MCTD and other ACTDs patients in whole blood samples. […] The present analysis revealed a statistically significant difference of global methylation between SLE and MCTD (p < 0.001), SLE and HC (p = 0.008), SSc and MCTD (p ≤ 0.001), and SSc and HC (p < 0.001), but neither between MCTD and HC (p = 0.09) nor SSc and SLE (p = 0.08). [...] Our study showed that patients with limited SSc had a significantly higher global methylation level when compared to diffuse SSc.
  • #32 Mixed Connective Tissue Disease as Different Entity: Global Methylation Aspect
    https://www.mdpi.com/1422-0067/24/20/15495
    Our data has shown that the level of global DNA methylation may not be a good diagnostic marker to distinguish MCTD from other ACTDs. […] Our study provided evidence of global DNA hypomethylation in MCTD patients. […] Our study illustrated for the first time the great potential of the global DNA methylation level of whole blood to discriminate MCTD patients and other ACTDs, which in the future may allow us to unequivocally state the existence or exclusion of MCTD as a separate disease entity and facilitate its diagnosis.
  • #33 Association study between immune-related miRNAs and mixed connective tissue disease | Arthritis Research & Therapy | Full Text
    https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-020-02403-9
    Mixed connective tissue disease (MCTD) is a rare condition that is distinguished by the presence of specific U1-RNP antibodies. Information about its etiopathology and diagnostics is still unclear. […] The exact cause for immune system dysregulation and chronic inflammation is ambiguous. A significant step in understanding the processes regulating the proper functioning of the immune system was the discovery of the microRNA (miRNA). miRNAs regulate the immune system and the immune response. Specific miRNAs modulate antigen presentation, clonal selection, Th skewing, Treg function, cytokine production, cytokine functions, recruitment of chemo-dependent inflammatory cells, antibody production, and non-immune cell mechanisms of tissue damage. […] The results of our casecontrol study indicate the possible significance of miR-146a and miR-143/145 in the susceptibility and clinical picture of MCTD.
  • #34 Association study between immune-related miRNAs and mixed connective tissue disease | Arthritis Research & Therapy | Full Text
    https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-020-02403-9
    Despite the growing knowledge of the importance of epigenetics in the regulation of immune response and the development of autoimmune diseases, there is still little research which relates to overlapping syndromes such as MCTD. Our research is the first study that examined the miRNA gene polymorphisms as well as expression in patients with MCTD. […] Distribution analysis revealed that out of all microRNAs studied only miR-146a rs2910164 C allele may result in a genetic predisposition to MCTD. […] Accordingly, to our result, the miRNA-146a rs2910164 CC genotype was significantly more common among MCTD patients with scleroderma. […] Our analysis showed that miR-143 rs353298 A/G genetic variant was associated with the occurrence of pericarditis/pleuritis and scleroderma. […] The limitations of this study include difficult biological materials and patients with different stories and treatment algorithms, which are difficult to diagnose.
  • #35 Association study between immune-related miRNAs and mixed connective tissue disease | Arthritis Research & Therapy | Full Text
    https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-020-02403-9
    Despite the growing knowledge of the importance of epigenetics in the regulation of immune response and the development of autoimmune diseases, there is still little research which relates to overlapping syndromes such as MCTD. Our research is the first study that examined the miRNA gene polymorphisms as well as expression in patients with MCTD. […] Distribution analysis revealed that out of all microRNAs studied only miR-146a rs2910164 C allele may result in a genetic predisposition to MCTD. […] Accordingly, to our result, the miRNA-146a rs2910164 CC genotype was significantly more common among MCTD patients with scleroderma. […] Our analysis showed that miR-143 rs353298 A/G genetic variant was associated with the occurrence of pericarditis/pleuritis and scleroderma. […] The limitations of this study include difficult biological materials and patients with different stories and treatment algorithms, which are difficult to diagnose.
  • #36 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    Levels of VEGF were higher in MCTD patients with pulmonary arterial hypertension (PAH) and myositis, possibly characterizing patients with a more severe course of disease. […] A murine model for MCTD has been developed, and it will assist in advancing preclinical and translational research in MCTD.
  • #37 Mixed Connective Tissue Disease (MCTD) | SpringerLink
    https://link.springer.com/10.1007%2F978-0-387-84828-0_369
    MCTD is an autoimmune syndrome in which high-titer autoantibodies to the U1 small nuclear ribonucleoprotein (anti-RNP) are present along with overlapping clinical manifestations of lupus, scleroderma, and/or inflammatory myositis. […] Greidinger EL, Hoffman RW. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31(3):43750. vi. […] Greidinger EL, Zang Y, Jaimes K, Hogenmiller S, Nassiri M, Bejarano P, Barber GN, Hoffman RW. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum. 2006;54(2):6619. […] Greidinger EL, Zang YJ, Jaimes K, Martinez L, Nassiri M, Hoffman RW. CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-transgenic murine model of mixed connective tissue disease. J Immunol. 2008;180(12):844454. […] Greidinger EL, Zang Y, Fernandez I, Berho M, Nassiri M, Martinez L, Hoffman RW. Tissue targeting of anti-RNP autoimmunity: effects of T cells and myeloid dendritic cells in a murine model. Arthritis Rheum. 2009;60(2):53442.
  • #38 Mixed Connective Tissue Disease (MCTD) | SpringerLink
    https://link.springer.com/10.1007%2F978-0-387-84828-0_369
    MCTD is an autoimmune syndrome in which high-titer autoantibodies to the U1 small nuclear ribonucleoprotein (anti-RNP) are present along with overlapping clinical manifestations of lupus, scleroderma, and/or inflammatory myositis. […] Greidinger EL, Hoffman RW. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31(3):43750. vi. […] Greidinger EL, Zang Y, Jaimes K, Hogenmiller S, Nassiri M, Bejarano P, Barber GN, Hoffman RW. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum. 2006;54(2):6619. […] Greidinger EL, Zang YJ, Jaimes K, Martinez L, Nassiri M, Hoffman RW. CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-transgenic murine model of mixed connective tissue disease. J Immunol. 2008;180(12):844454. […] Greidinger EL, Zang Y, Fernandez I, Berho M, Nassiri M, Martinez L, Hoffman RW. Tissue targeting of anti-RNP autoimmunity: effects of T cells and myeloid dendritic cells in a murine model. Arthritis Rheum. 2009;60(2):53442.
  • #39 Mixed Connective Tissue Disease (MCTD) | SpringerLink
    https://link.springer.com/10.1007%2F978-0-387-84828-0_369
    MCTD is an autoimmune syndrome in which high-titer autoantibodies to the U1 small nuclear ribonucleoprotein (anti-RNP) are present along with overlapping clinical manifestations of lupus, scleroderma, and/or inflammatory myositis. […] Greidinger EL, Hoffman RW. Autoantibodies in the pathogenesis of mixed connective tissue disease. Rheum Dis Clin North Am. 2005;31(3):43750. vi. […] Greidinger EL, Zang Y, Jaimes K, Hogenmiller S, Nassiri M, Bejarano P, Barber GN, Hoffman RW. A murine model of mixed connective tissue disease induced with U1 small nuclear RNP autoantigen. Arthritis Rheum. 2006;54(2):6619. […] Greidinger EL, Zang YJ, Jaimes K, Martinez L, Nassiri M, Hoffman RW. CD4+ T cells target epitopes residing within the RNA-binding domain of the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-transgenic murine model of mixed connective tissue disease. J Immunol. 2008;180(12):844454. […] Greidinger EL, Zang Y, Fernandez I, Berho M, Nassiri M, Martinez L, Hoffman RW. Tissue targeting of anti-RNP autoimmunity: effects of T cells and myeloid dendritic cells in a murine model. Arthritis Rheum. 2009;60(2):53442.
  • #40 Mixed connective tissue disease pathophysiology – wikidoc
    https://www.wikidoc.org/index.php/Mixed_connective_tissue_disease_pathophysiology
    MCTD is a systemic autoimmune disease that is characterized by overlapping symptoms of two or more systemic autoimmune diseases (SLE, RA, DM, polymyositis, and scleroderma) and the presence of antibodies against U1snRNP. […] Primary pathogenesis in MCTD include vasculopathy leading to tissue ischemia, immunological and inflammatory processes and fibrosis caused by excessive synthesis of collagen and other proteins of matrix. […] MCTD is characterized by clinical symptoms seen in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), dermatomyositis (DM), polymyositis, and scleroderma. […] Primary pathogenesis in MCTD include: vasculopathy leading to tissue ischemia, autoimmunity causes immunological and inflammatory, fibrosis caused by excessive synthesis of collagen and other proteins of matrix. […] In MCTD, U1-snRNP components play an important role for triggering immune responses. […] Two complications of pulmonary hypertension and interstitial lung disease are the most frequent causes of death.
  • #41 Better Survival in Patients With SSc-Mixed Connective Tissue Disease and SSc-Overlap vs SSc-Only – Rheumatology Advisor
    https://www.rheumatologyadvisor.com/news/better-survival-in-ssc-mixed-connective-tissue-disease-and-ssc-overlap-vs-ssc-only/
    There are significant clinical differences and outcomes between patients with systemic sclerosis (SSc)-mixed connective tissue disease (MCTD), SSc-overlap, and SSc-only, according to research results published in Arthritis Care and Research. […] Mixed connective tissue disease is defined by the presence of anti-ribonucleoprotein complex (RNP) antibody with 3 clinical features, including swollen fingers, synovitis, myositis, Raynaud phenomenon, or acrosclerosis. […] Kaplan-Meier curves showed better survival in the SSc-MCTD group compared with patients in the SSc-overlap or the SSc-only groups (P =.011); however, scleroderma-specific antibodies that were more reliable indicators of survival indicated that antinuclear antibody-centromere or anti-RNP conferred consistently better survival than anti-topoisomerase 1 (Scl)-70 or anti-RNA polymerase 3.
  • #42 Better Survival in Patients With SSc-Mixed Connective Tissue Disease and SSc-Overlap vs SSc-Only – Rheumatology Advisor
    https://www.rheumatologyadvisor.com/news/better-survival-in-ssc-mixed-connective-tissue-disease-and-ssc-overlap-vs-ssc-only/
    Overall, compared with SSc-only, SSc-MCTD and SSc-overlap groups combined had significantly better survival (P =.019). […] This study provides insights into the clinical characteristics of patients with SSc-MCTD, SSc overlap, and SSc-only, and shows that anti-RNP antibodies are associated with better survival than anti-Scl-70 and anti-RNA polymerase [3] antibodies, the researchers concluded.
  • #43
    https://link.springer.com/article/10.1007/s10067-022-06286-w
    Mixed connective tissue disease (MCTD) is a systemic, immune-mediated disorder exhibiting a broad spectrum of disease manifestations including symptoms of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), primary myositis (PM) or rheumatoid arthritis (RA), which underline the importance of high titres of anti-U1-snRNP autoantibodies for diagnosis. […] Evidence for MCTD as a distinct disorder has mainly come from research into genetics and immunology: HLA-typing studies identified characteristic risk alleles for MCTD compared to other CTDs or healthy controls. […] Immunologic studies have elucidated the role of anti-U1-snRNP autoantibodies in the pathogenesis of MCTD. […] As a disease with a broad spectrum of clinical manifestations, significant overlap with other rheumatic diseases, heterogeneous use of diagnostic criteria and low disease prevalence, MCTD represents a significant diagnostic challenge even for rheumatologists. […] Measurement of disease activity using SLEDAI-2 K and EUSTAR-AI further demonstrated a significantly better response to treatment of SLE-like than of SSc-like disease manifestations, which is consistent with previous data.
  • #44 The Type I Interferon Pathway’s Influence in Connective Tissue Disease – The Rheumatologist
    https://www.the-rheumatologist.org/article/the-type-i-interferon-pathways-influence-in-connective-tissue-disease/
    This serves as additional evidence that type I interferon plays a causal role in human autoimmune disease. […] Researchers still have many unanswered questions about both the upstream drivers of increased type I interferon and the downstream mechanisms by which it impacts disease initiation and propagation. […] Questions remain about when exactly the impact of type I interferon might be most important. […] Several biologic drugs that directly target the pathway have been studied in clinical trials. […] Most of the drug trials have demonstrated that patients with a higher interferon signature tend to respond to treatment. […] The need for new treatments in lupus is acute. […] At the clinical level, we need to better understand the role of RNA interferon signature or serum interferon inducible chemokines for predicting outcome.
  • #45 Mixed Connective Tissue Disease (MCTD): 6 Case Based Review
    https://clinmedjournals.org/articles/jmdt/journal-of-musculoskeletal-disorders-and-treatment-jmdt-6-080.php
    Mixed Connective Tissue Disease is an autoimmune clinical entity with characteristics of overlap syndrome including: Systemic Lupus Erythematosus, Rheumatoid Arthritis, Systemic Sclerosis, Polymyositis and Dermatomyositis. […] Although the controversy persists, after an extensive review of the literature we consider that Mixed Connective Tissue Disease is not a variant of lupus, but a different entity with a different course and prognosis. […] Extractable Nuclear Antigen (ENA) now called Ribonucleoproteins (RNP) are a group of cytoplasmic and nuclear antigens of which Anti-U1 RNP (Ribonucleoprotein) is the characteristic of MCTD. […] Autoimmunity to specific components of the spliceosome is the immunological characteristic of MCTD. […] The clinical features considered distinctive of MCTD are associated with the presence of antibodies with specificity of 70 kD, with an immunodominant epitope that encompasses amino acid residue 125 flanked by important conformational residues at positions 119 to 126.
  • #46 Mixed Connective Tissue Disease | Treatment & Management | Point of Care
    https://www.statpearls.com/point-of-care/25207
    Given the anti-U1-RNP antibody is the hallmark of MCTD, it is believed that the anti-U1-RNP antibody and its antigen play a role in the pathogenesis of MCTD. The U1-RNP complex is an intranuclear protein that converts pre-messenger RNA to mature RNA. This complex comprises 3 specific proteins A, C, and 70 kDa to which anti-U1 RNP antibodies bind. The 70 kDa antigen is the main target of the anti-RNP antibody in MCTD. The genetic association of MCTD with HLA-DR4 and DR2 phenotypes indicates the involvement of T-cell receptors and HLA molecules in the generation of anti-U1-RNP. […] Two main mechanisms have been proposed for the pathogenic role of anti-U1-RNP antibodies. The first mechanism involves direct binding to endothelial cells through U1-RNP peptides or recognition of nucleosome RNP fragments in endothelial cell apoptotic blebs. This mechanism may lead to the phenotype involving vascular diseases such as Raynaud phenomenon, skin sclerosis, and pulmonary hypertension. The second possible pathogenic mechanism is through immune complex formation, which can activate the complement cascade and lead to tissue inflammation and damage, such as myositis, arthritis, and interstitial lung disease.
  • #47 Mixed Connective-Tissue Disease (MCTD): Practice Essentials, Pathophysiology, Etiology
    https://emedicine.medscape.com/article/335815-overview
    The fundamental cause of MCTD remains unknown. Autoimmunity to components of the U1-70 kd snRNP is a hallmark of disease. Anti-RNP antibodies can precede overt clinical manifestations of MCTD, but overt disease generally develops within 1 year of anti-RNP antibody induction. The loss of T-lymphocyte and B-lymphocyte tolerance, due to cryptic self-antigens, abnormalities of apoptosis, or molecular mimicry by infectious agents, and driven by U1-RNA induced innate immune responses and other danger signal sensors induced by end-organ injury, are proposed current theories of pathogenesis. […] It is notable that the RNA component unique to the U1-small nuclear ribonucleoprotein, U1-RNA, is among the most prevalent RNAs present in cellular apoptotic debris, and that U1-RNA is an agonist for autoimmunity-associated endosomal Toll-like receptors, including TLR7 and TLR3. These observations promote the hypothesis that immune recognition of apoptotic debris may play a key role in the etiology of anti-RNP autoimmunity, as in MCTD.
  • #48 Towards early diagnosis of mixed connective tissue disease | ITT
    https://www.dovepress.com/towards-early-diagnosis-of-mixed-connective-tissue-disease-updated-per-peer-reviewed-fulltext-article-ITT
    Anti-U1-RNP can stimulate both mononuclear cells and autoreactive CD4+ cells, with an increased production of Interleukin (IL) 1 and IL6 (leading to autoimmune inflammation), but tissue injury is also sustained due to the direct action of the autoantibody on endothelial cells. […] This mechanism could explain the vascular involvement seen in MCTD, in particular Pulmonary Artery Hypertension (PAH). […] The presence of double stranded RNA in the U1 complex is responsible for the activation of innate immunity through Toll-like Receptor 3, activating also the innate immunity. […] Anti-U1RNP also seems to be able to activate immature dendritic cells via TLR7, inducing the production of Type I Interferon (IFN-1), in turn able to promote the activation of autoreactive T cells, with a down-regulation of regulatory T cells and the production of effector T cells, ultimately responsible of the tissue injury. […] IFN-1 also activates autoreactive T cells, leading to the production of autoantibodies.
  • #49 Interferons (IFN-A/-B/-G) Genetic Variants in Patients with Mixed Connective Tissue Disease (MCTD)
    https://www.mdpi.com/2077-0383/8/12/2046
    Although the detailed etiopathogenesis of systemic CTDs is not established, the growing volume of published studies has confirmed that excessive immunological activation with TLRs and IFNs is very important/one of the crucial pathogenic mechanisms of these diseases. […] Our results indicate that IFN-G genetic variants may be potential genetic biomarkers for MCTD susceptibility and severity. […] The present study demonstrates, for the first time, the association between IFN-A, IFN-B, and IFN-G genetic variants and MCTD risk, phenotype, and serological profile. […] Our results showed a significant association of the IFN-A rs10757212, IFN-A rs3758236, IFN-G rs2069705, and IFN-G rs2069718 gene polymorphisms with the occurrence of MCTD. […] Our results also demonstrated that the IFN-G genetic variant at position rs2069718 G/A might be associated with some clinical symptoms of MCTD, such as Raynaud’s Phenomenon, erosive arthritis, swollen hands and fingers, and sclerodactyly.
  • #50 Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease | Musculoskeletal Key
    https://musculoskeletalkey.com/mixed-connective-tissue-disease-and-undifferentiated-connective-tissue-disease-2/
    RNP-reactive CD4 + T cells have been identified from peripheral blood of MCTD patients. […] Both anti-RNP and anti-U1-RNA antibodies found in patients sera have, in most instances, undergone isotope switching to immunoglobulin G (IgG) subtypes. […] Also, there is dense lymphocyte infiltration, with many T cells found in the sites of tissue injury at autopsy and in biopsy specimens from patients. […] Findings have also shown that human RNP reactive T cells can provide B-cell help in vitro to anti-RNP autoantibody production. […] Vascular alterations result in some of the most severe clinical manifestations in patients with MCTD. […] Uncontrolled overexpression of angiogenic and angiostatic factors (vascular endothelial growth factor [VEGF] and endostatin) were found in adult MCTD patients.
  • #51 POS0880 OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH MIXED CONNECTIVE TISSUE DISEASE | Annals of the Rheumatic Diseases
    https://ard.bmj.com/content/83/Suppl_1/651.2
    The mechanism of vasculopathy associated with MCTD remains largely unknown. […] Our research indicates ocular vascular abnormalities in patient with MCTD, decreased retinal vessel density and lower choricapillaries flow. The results show the important role of OCTA in diagnosis and monitoring microvascular changes in MCTD patients.
  • #52 The Type I Interferon Pathway’s Influence in Connective Tissue Disease – The Rheumatologist
    https://www.the-rheumatologist.org/article/the-type-i-interferon-pathways-influence-in-connective-tissue-disease/
    This serves as additional evidence that type I interferon plays a causal role in human autoimmune disease. […] Researchers still have many unanswered questions about both the upstream drivers of increased type I interferon and the downstream mechanisms by which it impacts disease initiation and propagation. […] Questions remain about when exactly the impact of type I interferon might be most important. […] Several biologic drugs that directly target the pathway have been studied in clinical trials. […] Most of the drug trials have demonstrated that patients with a higher interferon signature tend to respond to treatment. […] The need for new treatments in lupus is acute. […] At the clinical level, we need to better understand the role of RNA interferon signature or serum interferon inducible chemokines for predicting outcome.
  • #53 Association study between immune-related miRNAs and mixed connective tissue disease | Arthritis Research & Therapy | Full Text
    https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-020-02403-9
    We believe that our study can be used as a base, or as part of a larger study or meta-analysis, which will show the differences or similarities between MCTD and other ACTDs, which in the future will allow us to unequivocally state the existence or exclusion of MCTD as a separate disease entity and facilitate its diagnosis.

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