Niedobór odporności pierwotny – Etiologia i przyczyny

Niedobór odporności pierwotny
Etiologia i przyczyny

Pierwotne niedobory odporności (PID) to heterogenna grupa chorób genetycznych, obejmująca ponad 550 zidentyfikowanych typów, charakteryzujących się wrodzonymi defektami w rozwoju i funkcjonowaniu układu immunologicznego. Mutacje genetyczne, dziedziczone autosomalnie dominująco, recesywnie lub sprzężone z chromosomem X, prowadzą do zaburzeń produkcji i funkcji komórek odpornościowych oraz białek, takich jak przeciwciała, receptory interleukin czy enzymy (np. deaminaza adenozyny). Przykłady obejmują SCID (często mutacja genu łańcucha gamma receptora IL-2), zespół DiGeorge’a (mikrodelecja 22q11.2), zespół hiper-IgM (defekt CD40L), czy przewlekłą chorobę ziarniniakową (defekt oksydazy NADPH). PID klasyfikuje się na niedobory komórek B (50-60% przypadków), T (5-10%), złożone niedobory komórek B i T, defekty fagocytów, niedobory dopełniacza (2%) oraz niedobory idiopatyczne. Diagnostyka molekularna, w tym sekwencjonowanie całego eksomu (WES), umożliwia identyfikację mutacji i precyzyjne rozpoznanie.

Etiologia niedoboru odporności pierwotnego

Niedobór odporności pierwotny (Primary Immunodeficiency, PID) odnosi się do dużej heterogenicznej grupy chorób genetycznych, w których część układu odpornościowego jest nieobecna lub nie funkcjonuje prawidłowo. Obecnie zidentyfikowano ponad 550 różnych typów pierwotnych niedoborów odporności, a ta liczba stale rośnie wraz z postępem badań genetycznych i molekularnych ¹². W przeciwieństwie do wtórnych niedoborów odporności, pierwotne niedobory odporności są wynikiem wrodzonych defektów w rozwoju i/lub funkcjonowaniu układu immunologicznego ³.

Podłoże genetyczne PID

Większość pierwotnych niedoborów odporności jest spowodowana mutacjami genetycznymi, które wpływają na rozwój i funkcjonowanie układu odpornościowego ¹². Te defekty genetyczne mogą być dziedziczone od jednego lub obojga rodziców, choć w niektórych przypadkach mogą pojawić się spontanicznie ¹². Problemy w kodzie genetycznym, który działa jako schemat produkcji komórek organizmu (DNA), powodują wiele z tych defektów układu odpornościowego ³.

Zaburzenia te są zazwyczaj obecne od urodzenia, chociaż objawy mogą pojawić się później w życiu, czasem nawet w okresie dojrzewania lub dorosłości ¹. Pierwotne niedobory odporności nie są spowodowane czynnikami środowiskowymi, lekami, urazami, dietą ani zdarzeniami występującymi podczas ciąży ².

Wzorce dziedziczenia PID

Istnieją dwa główne typy wzorców dziedziczenia dla zaburzeń niedoboru odporności: sprzężony z chromosomem X i autosomalny recesywny. Niewielka liczba zaburzeń jest dziedziczona w sposób autosomalny dominujący ¹. Mutacje na chromosomie X występują spontanicznie ze stosunkowo dużą częstotliwością. Oznacza to, że zaburzenie sprzężone z chromosomem X może wystąpić w rodzinie bez wcześniejszej historii tego zaburzenia, co ma miejsce w około 30% nowo zdiagnozowanych mężczyzn ².

Niedawno uznano, że niektóre pierwotne niedobory odporności są dziedziczone jako zaburzenia autosomalne dominujące. Jednym z przykładów jest zespół aktywowanej fosforyloinozytyd 3-kinazy delta (APDS), który powoduje zaburzenie podobne do pospolitego zmiennego niedoboru odporności ¹.

Około 60% osób z pierwotnymi zaburzeniami niedoboru odporności stanowią mężczyźni, co jest związane z dziedziczeniem sprzężonym z chromosomem X wielu z tych zespołów ¹.

Mutacje genetyczne powodujące PID

Pierwotne niedobory odporności są spowodowane uszkadzającymi wariantami linii zarodkowej w pojedynczych genach. Mutacje te mogą powodować chorobę poprzez zmianę kodowanego produktu genu, na przykład przez zniesienie lub zmniejszenie ekspresji i funkcji białka (null/hipomorficzne) lub modyfikację białka w celu uzyskania funkcji gain-of-function (GOF) ¹.

Mechanizmy choroby w PID zależą od charakteru wariantu, a także od sposobu dziedziczenia ¹. Monoalleliczne warianty mogą powodować chorobę przez haploinsuficjencję, dominację negatywną lub GOF. Natomiast bialleliczne uszkodzenia genetyczne (homozygotyczne, złożone heterozygotyczne) powodują cechy autosomalne recesywne (AR) przez utratę ekspresji, utratę funkcji (LOF), GOF, a nawet neomorficzną funkcję kodowanego białka ².

Na przykład ciężki złożony niedobór odporności (SCID) jest najczęściej spowodowany mutacją genu zlokalizowanego na chromosomie X w ponad 50% przypadków. Wadliwy gen koduje łańcuch gamma receptora interleukiny-2 (IL-2). Ten łańcuch tworzy molekularną część receptorów dla IL-2, IL-4, IL-7, IL-11, IL-15 i IL-21 ¹.

Z kolei w zespole nagich leukocytów występuje mutacja w genie kodującym transaktywator klasy II MHC (CIITA), co prowadzi do braku cząsteczki MHC klasy II na komórkach prezentujących antygen, w tym makrofagach i komórkach dendrytycznych ¹.

Klasyfikacja pierwotnych niedoborów odporności

Pierwotne niedobory odporności można sklasyfikować na podstawie części układu odpornościowego, która jest dotknięta defektem. Wyróżnia się sześć głównych grup ¹:

Niedobory komórek B i przeciwciał

Niedobory komórek B (przeciwciał) stanowią najczęstszą formę pierwotnych niedoborów odporności, odpowiadając za około 50-60% przypadków ¹². Te zaburzenia charakteryzują się niezdolnością do produkcji przeciwciał w wystarczającej ilości lub odpowiedniej jakości ¹.

Przykłady obejmują:

Agammaglobulinemię sprzężoną z chromosomem X (choroba Brutona) – defekt rozwojowy komórek B spowodowany mutacją genu kodującego kinazę tyrozynową Brutona (BTK) ¹²
Pospolity zmienny niedobór odporności (CVID) – heterogenna grupa zaburzeń charakteryzująca się różnym stopniem hipogammaglobulinemii ¹
Selektywny niedobór IgA – występuje u około 1 na 400 osób ¹
Zespół hiper-IgM – zaburzenie sprzężone z chromosomem X spowodowane defektem ligandu CD40, co uniemożliwia przełączanie klas przeciwciał ¹

Niedobory komórek T

Niedobory komórek T stanowią około 5-10% wrodzonych niedoborów odporności ¹. Obejmują one defekty w komórkowej odpowiedzi immunologicznej, które zwiększają podatność na zakażenia wewnątrzkomórkowe, takie jak wirusy, bakterie i pasożyty ¹.

Przykłady obejmują:

Zespół DiGeorge’a (aplazja grasicy) – spowodowany mikrodelecją na chromosomie 22 (22q11.2), charakteryzujący się defektami grasicy i często przytarczyc oraz serca, związanymi z dysfunkcją komórek T ¹²
Przewlekła kandydoza skórno-śluzówkowa – spowodowana kilkoma wrodzonymi defektami prowadzącymi do upośledzenia funkcji komórek T ¹
Zespół IPEX (immunodysregulacji, poliendokrynopatii, enteropatii, sprzężonej z chromosomem X) – spowodowany mutacją w genie FOXP3 ¹

Złożone niedobory komórek B i T

Większość defektów komórek T prowadzi do złożonych (komórek B i T) zaburzeń niedoboru odporności (CID) ¹. Te zaburzenia charakteryzują się defektami zarówno w humoralnej, jak i komórkowej odpowiedzi immunologicznej ¹.

Najbardziej znanym przykładem jest ciężki złożony niedobór odporności (SCID), potencjalnie śmiertelny stan charakteryzujący się brakiem funkcji limfocytów T i B ¹. SCID jest spowodowany różnymi mutacjami genetycznymi, w tym mutacjami w genach kodujących receptory interleukiny, deaminazę adenozyny lub nukleozydową fosforylazę ¹.

Inne przykłady obejmują:

Zespół Wiskotta-Aldricha – spowodowany mutacją genu WAS (dziedziczenie recesywne sprzężone z chromosomem X) ¹
Ataksja teleangiektazja – związana z krzywicą ¹
Zespół hiper-IgE autosomalny dominujący – spowodowany mutacją STAT3 ¹

Defekty fagocytów

Fagocyty (neutrofile i makrofagi) są kluczowe dla zwalczania zakażeń ¹. Zaburzenia fagocytów mogą być spowodowane deficytem liczby neutrofili lub upośledzeniem funkcji fagocytów ¹.

Przykłady obejmują:

Przewlekła choroba ziarniniakowa (CGD) – spowodowana defektami w układzie oksydazy NADPH fagocytów, w tym neutrofili i makrofagów, które zapobiegają produkcji rodników ponadtlenkowych w fagolizosomach ¹
Niedobór adhezji leukocytów typu 1 – dziedziczenie autosomalne recesywne ¹
Zespół Chédiaka-Higashiego – autosomalny recesywny; defekt genu regulatora transportu lizosomalnego (LYST) ¹
Niedobór mieloperoksydazy – autosomalna recesywna mutacja w genie MPO ¹

Niedobory dopełniacza

Niedobory dopełniacza są rzadkie (2% pierwotnych niedoborów odporności) i obejmują izolowane niedobory składników dopełniacza lub inhibitorów, które mogą być dziedziczne lub nabyte ¹. Te niedobory prowadzą do defektów w opsonizacji, fagocytozie i lizie patogenów oraz w usuwaniu kompleksów antygen-przeciwciało ².

Najpoważniejsze konsekwencje to:

Nawracające zakażenia spowodowane defektami opsonizacji ¹
Choroby autoimmunologiczne (np. toczeń rumieniowaty układowy, kłębuszkowe zapalenie nerek) spowodowane defektami w usuwaniu kompleksów antygen-przeciwciało ²

Przykłady obejmują:

Niedobór inhibitora esterazy C1 – dziedziczenie autosomalne dominujące ¹
Niedobór lektyny wiążącej mannozę – mutacje w genie MBL2 ¹

Niedobory idiopatyczne

To grupa pierwotnych niedoborów odporności, w przypadku których dokładna przyczyna genetyczna nie została jeszcze ustalona ¹. W miarę postępu technologii sekwencjonowania genów i badań, coraz więcej z tych zaburzeń jest identyfikowanych na poziomie molekularnym ¹.

Molekularne podstawy pierwotnych niedoborów odporności

Defekty genetyczne powodujące pierwotne niedobory odporności mogą wpływać na różne aspekty układu odpornościowego, w tym produkcję, funkcję i dystrybucję komórek odpornościowych i przeciwciał ¹.

Defekty szlaków sygnałowych

Wiele pierwotnych niedoborów odporności wynika z defektów w szlakach sygnałowych, które są niezbędne do prawidłowego rozwoju i funkcjonowania układu odpornościowego ¹. Mutacje w genach kodujących białka szlaków sygnałowych mogą prowadzić do różnych fenotypów niedoboru odporności.

Przykłady obejmują:

Mutacje w genie STAT1 wpływają na różnicowanie komórek Th17, które są podgrupą komórek T CD4+ zaangażowanych w odpowiedzi immunologiczne zależne od komórek nabłonkowych i neutrofili przeciwko drobnoustrojom pozakomórkowym i w patogenezie chorób autoimmunologicznych ¹
Mutacje w genie NIK (kinaza indukcji jądrowego czynnika κB) prowadzą do limfopenii komórek B i upośledzenia różnicowania komórek pamięci B ¹
Defekty w szlaku CD40/CD40L prowadzą do zespołu hiper-IgM, charakteryzującego się brakiem przełączania klas przeciwciał ¹

Defekty receptorów rozpoznających wzorce

Jednym z szybko rozwijających się obszarów badań immunologicznych są badania nad mutacjami genetycznymi dotyczącymi szlaków sygnałowych i receptorów rozpoznających wzorce (PRR) zaangażowanych w funkcję odporności wrodzonej, np. receptorów toll-podobnych (TLR), które są związane z ciężkimi fenotypami niedoboru odporności wrodzonej ¹.

Przykłady obejmują:

Niedobór receptora IL-12 – dziedziczenie autosomalne recesywne ¹
Niedobór MyD88 – dziedziczne zaburzenie, w którym osoby cierpią na nawracające i ciężkie ropne (wytwarzające ropę) zakażenia bakteryjne ¹

Defekty enzymów

Niektóre pierwotne niedobory odporności są spowodowane mutacjami w genach kodujących enzymy niezbędne do prawidłowego rozwoju i funkcjonowania układu odpornościowego.

Przykłady obejmują:

Niedobór deaminazy adenozyny (ADA-SCID) – autosomalne recesywne zaburzenie metaboliczne powodujące niedobór odporności. Wadliwy gen odziedziczony od obojga rodziców zatrzymuje produkcję niezbędnego białka zwanego deaminazą adenozyny (ADA), które jest szczególnie ważne dla tworzenia limfocytów i funkcjonującego układu odpornościowego ¹
Mutacje w genach kodujących RAG1 lub RAG2 powodują autosomalną recesywną postać SCID ¹

Czynniki ryzyka pierwotnych niedoborów odporności

Głównym czynnikiem ryzyka rozwoju pierwotnego niedoboru odporności jest historia rodzinna tych chorób ¹. Jeżeli ktoś inny w rodzinie ma PID, dziecko z większym prawdopodobieństwem również będzie miało takie zaburzenie ¹.

Czynniki genetyczne

Ponieważ większość PID jest spowodowana defektami genetycznymi, historia rodzinna jest najważniejszym znanym czynnikiem ryzyka ¹. Dzieci, które mają rodziców lub rodzeństwo z PID, mają zwiększone ryzyko rozwinięcia podobnego zaburzenia.

W niektórych przypadkach ryzyko to może być zwiększone przez konsanguinizm (małżeństwa między kuzynami lub bliskimi krewnymi). W Jordanii konsanguinizm jest bardziej rozpowszechniony na obszarach wiejskich (~40%) niż w stolicy, Ammanie, gdzie poziomy te wynoszą ~25,5% ¹.

Dziecko, które zostało zdiagnozowane z nawracającymi poważnymi infekcjami, które ma pozytywną historię rodzinną tego typu chorób lub które pochodzi z grupy etnicznej związanej z wyższym pokrewieństwem rodziców (np. północna i subsaharyjska Afryka; Bliski Wschód; części zachodniej, środkowej i południowej Azji) powinno być przebadane w kierunku choroby immunologicznej ¹.

Nieinfekcyjne manifestacje PID

Chociaż większość pierwotnych niedoborów odporności objawia się zwiększoną podatnością na zakażenia, wiele z nich może również prowadzić do chorób autoimmunologicznych, autoinflammacyjnych, alergii, niewydolności szpiku kostnego i/lub nowotworów ¹².

Na przykład niedobory dopełniacza mogą zwiększać ryzyko chorób autoimmunologicznych, a niektóre pierwotne niedobory odporności mogą zwiększać ryzyko rozwoju nowotworów ¹.

Podsumowanie etiologii PID

Pierwotne niedobory odporności są spowodowane mutacjami genetycznymi, które wpływają na rozwój i funkcjonowanie układu odpornościowego. Te mutacje mogą być dziedziczone od jednego lub obojga rodziców, choć w niektórych przypadkach mogą pojawić się spontanicznie ¹².

Mutacje genetyczne mogą zakłócać produkcję komórek lub białek odpornościowych, które są niezbędne do obrony organizmu przed zakażeniami. Niektóre mutacje mogą prowadzić do częściowej dysfunkcji układu odpornościowego, podczas gdy inne mogą powodować całkowity brak lub nieprawidłowe funkcjonowanie komórek odpornościowych, co sprawia, że osoby są bardzo podatne na zakażenia ¹.

Obecnie zidentyfikowano ponad 550 różnych typów pierwotnych niedoborów odporności, a ta liczba stale rośnie wraz z postępem badań genetycznych ¹. PID mogą zostać szeroko sklasyfikowane na podstawie części układu odpornościowego, która jest dotknięta: niedobory komórek B (przeciwciał), niedobory komórek T, złożone niedobory komórek B i T, defekty fagocytów, niedobory dopełniacza oraz niedobory idiopatyczne (nieznane) ¹.

Zrozumienie molekularnych i genetycznych podstaw pierwotnych niedoborów odporności jest niezbędne dla opracowania ukierunkowanych terapii i poprawy wyników leczenia pacjentów ¹. Postępy w technologiach sekwencjonowania, takich jak sekwencjonowanie całego eksomu (WES), znacząco przyczyniły się do identyfikacji nowych genów przyczynowych w przypadkach PID ¹.

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Materiały źródłowe

#1 What is PI? | Immune Deficiency Foundation
https://primaryimmune.org/understanding-primary-immunodeficiency/what-is-pi
Primary immunodeficiencies (PIs) are a group of more than 550 rare, chronic conditions where a part of the body’s immune system is missing or does not function correctly. […] PI conditions are caused by genetic variants and can affect anyone, regardless of age, gender, or ethnicity. […] There are more than 550 primary immunodeficiencies with distinct definitions, causes, and symptoms.
#1 Primary Immunodeficiency: Symptoms, Causes, Diagnosis, Treatment, and Prevention
https://www.everydayhealth.com/genetic-diseases/primary-immunodeficiency/
Primary immunodeficiency is caused by genetic changes that affect one or many components of the immune system, including cells and proteins. The genetic changes can make the immune system less active than normal, defective, or totally absent. […] Most, but not all, of these genetic changes are inherited. So although anyone can develop primary immunodeficiency, it’s more likely to happen in people with a biological family history. […] Genetic mutations cause most types of PI. Since primary immunodeficiency is usually inherited and present from birth, it’s not preventable.
#1 Primary immunodeficiency | Beacon Health System
https://www.beaconhealthsystem.org/library/diseases-and-conditions/primary-immunodeficiency?content_id=CON-20376887
Many primary immunodeficiency disorders are inherited passed down from one or both parents. Problems in the genetic code that acts as a blueprint for producing the cells of the body (DNA) cause many of these immune system defects. […] There are more than 300 types of primary immunodeficiency disorders, and researchers continue to identify more. They can be broadly classified into six groups based on the part of the immune system that’s affected: B cell (antibody) deficiencies, T cell deficiencies, Combination B and T cell deficiencies, Defective phagocytes, Complement deficiencies, Unknown (idiopathic).
#1 Primary Immunodeficiency | Boston Children’s Hospital
https://www.childrenshospital.org/conditions/primary-immunodeficiency
Primary immunodeficiency disorders (PIDDs) are a group of inherited conditions affecting the immune system, due to a lack of, or dysfunction of white blood cells, which have important roles in fighting infections. […] PIDDs are genetic disorders, meaning that every cell in the body carries the mutated gene, responsible for their PID. […] Since PIDDs are caused by genetic changes, these may be inherited. […] PIDDs are present at birth, although the symptoms may not begin until later in life, sometimes even in teenage years or adulthood. Thus, PIDDs are not caused by environmental exposures, medications, trauma, diet or events occurring during pregnancy. […] PIDDs are genetic disorders, meaning that every cell in the child’s body usually carries a defective or mutated gene that causes the disease. […] No. So far, research only shows genetics as the cause for PID.
#1 Genetic aspects of primary immunodeficiency | Great Ormond Street Hospital
https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/genetic-aspects-primary-immunodeficiency/
Primary immunodeficiency disorders are the result of defects in an individuals genetic make-up. These defects are mistakes that occur in genes and are passed from generation to generation. […] In an increasing number of immunodeficiency disorders, the precise mistake in the relevant gene can now be identified in the laboratory, and this not only helps to determine the best treatment but also means that accurate counselling can be offered to the family, and screening tests can be offered in pregnancy if requested. […] There are two main types of inheritance pattern for immunodeficiency disorders: X-linked and autosomal recessive. A small number of disorders are inherited in an autosomal dominant pattern. […] Mutations on the X chromosome occur spontaneously with a relatively high frequency. This means that an X-linked disorder can occur in a family with no previous history of the disorder, and this is the case in approximately 30 per cent of newly diagnosed males.
#1 Genetic aspects of primary immunodeficiency | Great Ormond Street Hospital
https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/genetic-aspects-primary-immunodeficiency/
Recently it has been recognised that some primary immunodeficiencies are inherited as autosomal dominant disorders. One example is activated phosphoinositide 3 kinase delta syndrome (APDS), which causes a common variable immunodeficiency-like disorder. It is likely that many more will be identified with further genetic research. […] Increasing numbers of immunodeficiencies are being defined at a molecular or genetic level. Currently there are over 300 known disorders, and it is now possible to determine the underlying cause in many cases. […] In cases that do not fit a typical pattern or where initial genetic testing does not make a diagnosis, there are now other sophisticated techniques that may identify the underlying genetic cause. […] In families where an immunodeficiency has been recognised, some parents may wish to know whether future babies are affected by the disorder, particularly if it is one of the more severe forms.
#1 Immunodeficiency (Primary and Secondary) | Doctor
https://patient.info/doctor/immunodeficiency-primary-and-secondary
Mostly these are inherited single-gene disorders that present in infancy or early childhood with the exception of common variable immunodeficiency which usually occurs in adults. […] Mutations/deletions of genes governing stem cell differentiation have been identified and over 250 disorders have been genetically identified with new disorders continually being described. […] Once thought to be rare, symptomatic primary immunodeficiencies are now considered to range from 1:500 to 1:500,000 in the general population in the USA and Europe. […] The age of presentation varies widely. […] 70% occur in males due to X-linked inheritance in many syndromes. […] B-cell defects account for 50% of primary immunodeficiency. […] T-cell defects account for 30%, phagocytic deficiencies 18% and complement deficiencies 2%. Knowledge about the function and diversity of B cells in health and disease has now become quite detailed but there is still much to learn.
#1
https://link.springer.com/article/10.1007/s10875-022-01289-3
We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. […] Inborn errors of immunity (IEI) are caused by damaging germline variants in single genes. IEI present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy. […] Genetic variants cause disease by altering the encoded gene product, such as by abolishing or reducing protein expression and function (null/hypomorphic) or modifying the protein to acquire gain-of-function (GOF).
#1
https://link.springer.com/article/10.1007/s10875-022-01289-3
Mechanisms of disease in IEI depend on the nature of the variant as well as the mode of inheritance. […] Thus, monoallelic variants can cause disease by haploinsufficiency, negative dominance, or GOF. In contrast, biallelic genetic lesions (homozygous, compound heterozygous) cause autosomal recessive (AR) traits by loss of expression, loss of function (LOF), GOF, or even neomorphic function of the encoded protein, while X-linked recessive traits arise from LOF or GOF variants on the X chromosome, either in hemizygosity in males, or homozygous state in females. […] The fact that some monogenic variants are pathogenic clearly highlights the non-redundant and fundamental roles of individual genes and proteins, and associated pathways and cell types, in the development and function of leukocytes and non-hematopoietic cells that contribute to immune homeostasis and host defense.
#1 Immunodeficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/23390
Primary immunodeficiency diseases result from intrinsic defects in immune cells, including T cells, complement components, and phagocytes. Recurrent pneumonia caused by extracellular bacteria suggests antibody deficiency. On the other hand, recurrent fungal infections may be caused by a lack of T lymphocytes. […] Severe combined immunodeficiency disorders (SCID) are incompatible with life, and affected children usually die within the first 2 years. SCID is more common in the male. It is caused by a gene defect on the X chromosome in more than 50% of cases. The defective gene encodes the gamma chain of the interleukin-2 (IL-2) receptor. This chain forms a molecular part of the receptors for IL-2, IL-4, IL-7, IL-11, IL-15, and IL-21. On the other hand, few cases of SCID are caused by defective genes that encode for adenosine deaminase or nucleoside phosphorylase. The deficiency of these enzymes causes ribonucleotide reductase inhibition leading to a defect in DNA synthesis and cell replication. Mutation in the genes encoding RAG1 or RAG2 causes an autosomal recessive form of SCID.
#1 Immunodeficiency | Treatment & Management | Point of Care
https://www.statpearls.com/point-of-care/23390
In the bare leukocyte syndrome, there is a mutation in the gene that encodes for the MHC class II transactivator (CIITA), resulting in the absence of class-II MHC molecule on antigen-presenting cells including macrophages and dendritic cells. A mutation in the gene that encodes for a transport-associated protein (TAP) results in the lack of class-I MHC molecule expression, which is manifested by a deficiency of CD8+ T lymphocytes. […] Secondary immunodeficiency may be caused by drugs, including steroids, cyclophosphamide, azathioprine, mycophenolate, methotrexate, leflunomide, ciclosporin, tacrolimus, and rapamycin, which affect the functions of both T and B lymphocytes. Viral infections can cause immunodeficiency. For example, HIV causes AIDS, which mainly affects CD4+T cells and downregulates cellular immune responses that produce opportunistic infections and cancers, which are threatening to human health.
#1 Primary Immunodeficiency: Types & Symptoms
https://my.clevelandclinic.org/health/diseases/17964-primary-immunodeficiency
Primary immunodeficiency refers to a group of more than 400 disorders that affect your immune system. These disorders prevent your immune system from functioning properly. This can make you more susceptible to infection and certain diseases, including autoimmune diseases and cancers. […] Genetic mutations (changes) cause primary immunodeficiency. Theyre usually inherited, or passed down, within families, but can sometimes pop up sporadically. […] Primary immunodeficiency results from genetic mutations affecting one or several components of your immune system, including cells and proteins. These mutations may cause parts of your immune system to be: Less active than usual. Defective. Totally absent. […] In 50% to 60% of cases, primary immunodeficiency relates to defects in B lymphocytes (B cells). These immune system cells make antibodies, specific proteins in your body. Your immune system uses antibodies to destroy pathogens (disease-causing agents) like bacteria or viruses. […] Genetic mutations cause most PIDD disorders, so theres no way to prevent them. If primary immunodeficiency runs in your family, you may want to consider genetic counseling.
#1 Immunodeficiency (Primary and Secondary) | Doctor
https://patient.info/doctor/immunodeficiency-primary-and-secondary
The conditions are sometimes classified according to which component is faulty (T cells, B cells, phagocytic cells or complement) or according to individual clinical syndromes. […] One study found that the four most common primary immunodeficiencies seen in paediatric practice (apart from physiological hypogammaglobulinaemia of infancy) were transient hypogammaglobulinaemia of infancy (THI), IgG subclass deficiency, partial antibody deficiency with impaired polysaccharide responsiveness (IPR) and selective IgA deficiency (IgAD). […] Antibody deficiency syndromes: this is a group of conditions characterised by an inability to produce antibodies in sufficient quantity or of sufficient quality. […] Common variable immunodeficiency: this is a heterogeneous syndrome characterised by various degrees of hypogammaglobulinaemia, commonly associated with autoimmunity.
#1 Primary Immunodeficiencies | Immunopaedia
https://www.immunopaedia.org.za/immunology/special-focus-area/1-primary-immunodeficiencies/
Severe combined immunodeficiency (SCID) is a collection of severe heritable genetic immunodeficiency disorders in which both arms (B cells and T cells) of the adaptive immune system may be crippled due to a defect in one of several possible genes. […] The prototype for the most common form of SCID has been considered to be the X-linked (SCID-XL) form due to mutations in the shared IL-2 common gamma chain receptor (IL-2Rc, Xq13) found in receptors for IL-2, IL-15, IL-4, IL-7, IL-9, and IL-21. […] The major B cell defects can be divided into three major categories of antibody deficiencies: (1) defects in early B cell development, (2) hyper-IgM syndromes (also called class-switch recombination defects), and (3) common variable immunodeficiency (CVID). […] First described in 1952 by Bruton, severe X-linked agammaglobulinemia (XLA) has been the paradigm for understanding the pure role of the B cell in immune function. […] The disease is now known to be due to defects in a tyrosine kinase, Bruton tyrosine kinase, BTK (MIM #300300).
#1 Immunodeficiency (Primary and Secondary) | Doctor
https://patient.info/doctor/immunodeficiency-primary-and-secondary
X-linked (Bruton’s agammoglobulinaemia): the agammaglobulinaemia is an X-linked immunodeficiency in which there is a failure to produce mature B-lymphocyte cells. […] Selective IgAD occurs in about 1/400 people. […] Cell-mediated immunity can be subject to a number of genetic defects affecting the function of the T cells. […] Thymic aplasia (DiGeorge syndrome): there are genetic defects of the thymus and often the parathyroid glands and heart, associated with T-cell dysfunction and significant immune deficiency. […] Severe combined immunodeficiency disease: this is in fact a group of rare congenital diseases in which there is severe and usually fatal immune deficiency. […] A wide range of inherited immunodeficiency conditions has been identified, many involving a single gene.
#1 Immunodeficiency – Primary – Secondary – TeachMePhysiology
https://teachmephysiology.com/immune-system/immune-responses/immunodeficiency/
Hyper-IgM syndrome is an X-linked recessive disorder caused by a defect in the CD40 ligand. This prevents class switching, meaning B cells can’t switch the production of IgM antibodies to IgG, IgA or IgE types. […] Common variable immunodeficiency is an umbrella term for antibody deficiency where the genetic cause is unknown. The hypothesis behind this disease is that there is a genetic mutation, but an infectious trigger is required for it to manifest. […] T cell deficiency can be due to reduced T cell counts, or impaired activity. This predisposes the sufferer to severe infections by intracellular parasites, bacteria and viruses. […] Neutrophil defects can be due to a deficiency in neutrophil counts, or an impairment of neutrophil function. […] Defects in each of the complement pathways have different implications for the immune system. Deficiency in the classical pathway causes a build up of immune complexes in tissues and an associated inflammatory response.
#1 Congenital immunodeficiency disorders – Knowledge @ AMBOSS
https://www.amboss.com/us/knowledge/congenital-immunodeficiency-disorders/
X-linked (Bruton) agammaglobulinemia: defect of Bruton tyrosine kinase (BTK) expressed in B cells complete deficiency of mature B cells. […] Selective IgA deficiency: Etiology: unknown. […] Common variable immunodeficiency: Etiology: Most cases are sporadic with no known family history. […] T-cell defects (cellular immunity deficiencies) are responsible for 510% of congenital immunodeficiencies. […] DiGeorge syndrome: Etiology: autosomal dominant; microdeletion at chromosome 22 (22q11.2). […] Autosomal dominant hyperimmunoglobulin E syndrome: Etiology: autosomal dominant; STAT3 mutation Th17 cells neutrophil chemotaxis. […] IL-12 receptor deficiency: Etiology: autosomal recessive. […] Chronic mucocutaneous candidiasis: Etiology: Several congenital defects that result in impaired T-cell function.
#1 Primary Immunodeficiencies (PIDs), Primary Immune Regulatory Disorders (PIRDs) and White Blood Cell Disorders | Memorial Sloan Kettering Cancer Center
https://www.mskcc.org/pediatrics/cancer-care/types/pediatric-blood-disorders/about-pediatric-blood-disorders/primary-immunodeficiencies-pids-primary-immune-regulatory-disorders-pirds-and-white-blood-cell-disorders
Wiskott-Aldrich syndrome is caused by a genetic mutation (change), and mostly affects males. […] Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a rare autoimmune disease. It only affects males. Symptoms usually start during a babys first 6 months. A child may have severe diarrhea, skin conditions (such as erythroderma, eczema, or psoriasis), and thyroid disease (thyroiditis). Boys with IPEX syndrome have mutations in a gene called the FOXP3 gene. […] X-linked inhibitor of apoptosis protein (XIAP) deficiency is also known as X-linked lymphoproliferative (XLP) disease. It is a rare disorder that almost always only affects males. It causes the body to have too strong an immune response to a very common virus called Epstein-Barr virus (EBV).
#1 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text
https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5
The treatment of PIDs is complex and generally requires both supportive and definitive strategies. […] Most T-cell defects lead to combined (B- and T-cell) immunodeficiency disorders (CIDs). […] Defects in the development and function of any of these elements of innate immunity may lead to PIDs. […] The mainstay of therapy for most B-cell (antibody-deficiency) disorders is intravenous (IV) or subcutaneous Ig replacement therapy; in fact, many patients will require this treatment indefinitely. […] There is currently no standardized approach to the use of prophylactic antibiotics in patients with established PIDs since randomized, controlled studies in this area are lacking. […] The prognosis of patients with PIDs varies depending on the etiology of the disorder. […] PID refers to a heterogeneous group of disorders that result from defects in immune system development and/or function.
#1 Types of PI | Immune Deficiency Foundation
https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi
Activated PI3K delta syndrome (APDS) is a rare primary immunodeficiency (PI) that is often misdiagnosed as CVID or another antibody deficiency. […] People with agammaglobulinemia can’t produce antibodies, which are an important part of the body’s defense against germs. […] Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1) or polyglandular autoimmune (PGA) syndrome type-1, is a primary immunodeficiency disease caused by variants in the autoimmune regulator (AIRE) gene. […] Combined immune deficiencies (CID) are a group of primary immunodeficiencies in which both T cells and B cells of the adaptive immune system are either low or function poorly. […] Common variable immune deficiency (CVID), previously known as adult-onset hypogammaglobulinemia, is one of the most frequently diagnosed primary immunodeficiencies. It is characterized by low levels of serum antibodies, which cause an increased susceptibility to infection.
#1 Types of PI | Immune Deficiency Foundation
https://primaryimmune.org/understanding-primary-immunodeficiency/types-of-pi
Congenital athymia is an ultra-rare condition in which children are born without a thymus, causing severe immunodeficiency and immune dysregulation. […] Severe combined immune deficiency (SCID) is a life-threatening primary immunodeficiency (PI), with a combined absence of T cell and B cell function. There are at least 20 different genetic variants that can cause SCID. […] Individuals with specific antibody deficiency have normal levels of antibodies (immunoglobulins) but cannot produce antibodies to specific types of microorganisms that cause respiratory infections. […] Primary immune regulatory disorders (PIRD) are characterized by a disturbance of immune tolerance and excessive inflammation. […] ZAP-70 deficiency is a rare autosomal recessive combined immunodeficiency. Peripheral T cells from individuals with ZAP-70 deficiency demonstrate defective T cell signaling and have an autoreactive phenotype. Indeed, several individuals have presented with autoimmune disorders.
#1 Congenital immunodeficiency disorders – Knowledge @ AMBOSS
https://www.amboss.com/us/knowledge/congenital-immunodeficiency-disorders/
IPEX syndrome: Etiology: X-linked recessive type of inheritance. […] Severe combined immunodeficiency: Etiology: various mutations, the most common of which are: X-linked recessive: mutations in the gene encoding the common gamma chain defective IL-2R gamma chain receptor linked to JAK3. […] Wiskott-Aldrich syndrome: Etiology: mutated WAS gene (X-linked recessive inheritance). […] Hyper-IgM syndrome: Etiology: X-linked recessive inheritance. […] Chronic granulomatous disease: Etiology: X-linked recessive or autosomal recessive inheritance. […] Leukocyte adhesion deficiency type 1: Etiology: Autosomal recessive inheritance. […] Chdiak-Higashi syndrome: Etiology: autosomal recessive; defective lysosomal trafficking regulator (LYST) gene. […] Myeloperoxidase deficiency: Etiology: autosomal recessive mutation in the MPO gene.
#1 Skeletal and Joint Manifestations of Primary Immunodeficiency Diseases
https://symbiosisonlinepublishing.com/immunology/immunology45.php
In SCID, a number of patients developing osteomyelitis following BCG vaccination have been reported. […] A T-B+NK+ SCID patient developed Mycobacteria marinum arthritis and osteomyelitis. […] Reticular dysgenesis is associated with bone anomalies of square shaped scapular tips and cupped costochondral junctions. […] Characteristic skeletal changes of anterior rib junction, metaphyseal changes, and scapular squaring have been reported in SCID due to adenosine deaminase deficiency. […] Chronic adenoviral arthritis and microcephaly have been reported in Cernunnos deficiency. […] In Wiskott- Aldrich syndrome, 29% of patients have aseptic arthritis. […] Ataxia Telangiectasia has been associated with rickets where all three members of a family had rickets. […] Ataxia Telangiectasia-like syndrome has been associated with microcephaly in 40% of patients.
#1 Primary Immunodeficiency
https://mobile.fpnotebook.com/ID/Immune/PrmryImndfcncy.htm
Genetic abnormalities affecting T-Cells, B-Cells, Phagocytes or Complement […] Antibody or humoral (B-Cell Disorder): 78% of cases in U.S. (55% in Europe) […] Present after 3 months of age (when maternal antibodies are no longer present) […] B Cell deficiency or maturation defect results in Antibody deficiency […] Recurrent respiratory (ears, sinus, lungs) infections with encapsulated organisms […] Severe T cell deficiency causes B Cell dysfunction […] Most T-Cell Disorders are mixed T-Cell and B-Cell Disorders as B-Cells rely on T-Cells […] Phagocytes (Neutrophils and Macrophages) are critical to clearing infections […] Disorders of Neutrophils or Monocytes/Macrophages […] Autoimmune Condition or Rheumatologic Condition (associated with C1-C4 deficiencies) […] Recurrent encapsulated organism, esp. pyogenic infections (manifestations vary depending on missing complement type)
#1 Primary Immunodeficiencies | Immunopaedia
https://www.immunopaedia.org.za/immunology/special-focus-area/1-primary-immunodeficiencies/
The underlying defect is impaired generation of activated forms of oxygen, i.e., superoxide (O2) and hydrogen peroxide (H2O2) due to a variety of enzymatic defects involving the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system. […] Mutations in gp91phox, p22phox, p47phox, and p67phox cause chronic granulomatous disease (CGD), characterized by recurrent life-threatening infections due to catalase-positive bacteria and fungi and granulomatous complications. […] These molecular lesions are responsible for the clinical manifestations resulting from an impaired step in the inflammatory process, namely, the emigration of leukocytes from the blood vessels to sites of infection, which requires adhesion of leukocytes to the endothelium. […] One of the most rapidly developing areas of immunologic research that is finding clinical applicability is being directed to the study of genetic mutations involving signaling pathways and pattern recognition receptors (PRRs) involved in innate immune function, e.g., TLRs that are associated with severe innate immunodeficiency phenotypes.
#1 Overview of Immunodeficiency Disorders – Immunology; Allergic Disorders – MSD Manual Professional Edition
https://www.msdmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders
Treatment and prognosis of primary immunodeficiency disorders depend on the specific disorder. […] Complement deficiencies are rare (2% of primary immunodeficiencies); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired. The deficiencies result in defective opsonization, phagocytosis, and lysis of pathogens and in defective clearance of antigen-antibody complexes. […] The most serious consequences are Recurrent infection, which is due to defective opsonization, Autoimmune disorders (eg, systemic lupus erythematosus, glomerulonephritis), which are due to defective clearance of antigen-antibody complexes.
#1 Congenital immunodeficiency disorders – Knowledge @ AMBOSS
https://www.amboss.com/us/knowledge/congenital-immunodeficiency-disorders/
Severe congenital neutropenia: Etiology: Autosomal dominant, autosomal recessive, or X-linked recessive inheritance. […] Complement component deficiencies are a group of rare inherited genetic conditions characterized by absent or abnormal complement component proteins, which increases the risk of recurrent bacterial infections and autoimmune conditions. […] C1 esterase inhibitor deficiency: Etiology: Autosomal dominant inheritance. […] Mannose-binding lectin deficiency: Etiology: mutations in the MBL2 gene.
#1 What Is Primary Immunodeficiency?
https://www.icliniq.com/articles/immune-disorders/primary-immunodeficiency
Primary immunodeficiency (PI) is caused by genetic mutations that affect the development and function of the immune system. […] The specific genetic mutations responsible for PI can affect different aspects of the immune system, including the production, function, and distribution of immune cells and antibodies. […] In some cases, PI may be inherited in an autosomal recessive or X-linked pattern, which means that both copies of a gene (one from each parent) must be affected for the disorder to manifest. […] While PI is primarily a genetic disorder, environmental factors such as exposure to certain viruses or toxins may also contribute to the development of some forms of PI. […] In conclusion, primary immunodeficiency (PI) is caused by genetic mutations that impair the immune system’s ability to fight infections. […] PI can be inherited in an autosomal recessive or X-linked pattern, but environmental factors such as exposure to certain viruses or toxins may also contribute to its development.
#1 Genetic causes of primary immunodeficiency in the Jordanian population
https://www.spandidos-publications.com/10.3892/br.2024.1848
In the present study, the genetic underpinnings of PIDs in 9 Jordanian patients were explored, identifying mutations in key immunological genes, including STAT1/2, MBL2, TYK2, UNG, TNIP1, CARMIL2 and ELANE, as well as a 9-bp insertion in IL17RC, and one frameshift and nonsense mutation in the same exon in GPSM1. […] A salient factor influencing the incidence of novel mutations is consanguinity. In Jordan, consanguinity is more prevalent in rural areas (~40%) than in its capital, Amman, where these levels are ~25.5%. […] Despite the high rate of consanguinity (4 out of 9 patients), only two homozygous variants were identified, with only one potentially linked to an IEI. This can be explained by considering several factors related to genetic diversity, the complexity of inheritance patterns and the nature of the diseases involved. […] The mutation in STAT1 affects the differentiation of Th17 cells, which are a subset of CD4+ T cells involved in epithelial cell- and neutrophil-mediated immune responses against extracellular microbes and in the pathogenesis of autoimmune diseases.
#1 Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity | Nature Communications
https://www.nature.com/articles/ncomms6360
Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. […] Here we report a combined immunodeficiency syndrome caused by biallelic mutations in the gene encoding NIK, encompassing B-cell lymphopenia and impaired memory B-cell differentiation. […] We show that human functional NIK deficiency recapitulates phenotypes described in the mouse studies including B-cell lymphopenia, impaired CSR and SHM, decreased marginal zone and memory B cells, and hypogammaglobulinemia. […] We identify patients with biallelic mutation in NIK, leading to loss-of-function of the kinase function of NIK. […] The NIKPro565Arg loss-of-function mutant causes a partial block of B-cell development between transitional and naive mature B-cell stages accompanied by impaired survival of mature peripheral B cells. […] NIK has not been linked to NK-cell function so far. […] Functional NIK deficiency causes defective CD40 signalling in monocytes as well. […] In sum, we identify functional NIK deficiency as a novel, pervasive combined primary immunodeficiency syndrome.
#1 Types of PI – Immunodeficiency Canada
https://immunodeficiency.ca/primary-immunodeficiency/types-of-pi/
Deficiency of CD45 is a catalyst for the condition SCID (Severe Combined Immunodeficiency). […] The condition Severe Combined Immunodeficiency can occur for many reasons; one of these reasons is the deficiency of Janus Kinase 3. […] Deficiency of the Alpha Chain of the IL-7 Receptor is another form of Severe Combined Immunodeficiency. […] DiGeorge Syndrome, otherwise known as 22q11.2 deletion syndrome, varies wildly between cases and can have a multitude of symptoms. […] A major symptom of DiGeorge Syndrome is the deficient immune system. […] The condition is suspected when a thymic tumor is seen on a chest X-ray. […] The condition is characterized by low immunoglobulins, along with a thymic tumor (thymoma). […] MyD88 deficiency is an inherited disorder where individuals suffer from recurrent and severe pyogenic (produces pus) bacterial infections.
#1 Types of PI – Immunodeficiency Canada
https://immunodeficiency.ca/primary-immunodeficiency/types-of-pi/
Primary Immunodeficiency (PI) is an umbrella term for over 350 genetic defects and disorders of the immune system recognized by the World Health Organization. […] Primary Immunodeficiency is not considered a rare disease as a category, but each individual form of PI is rare. […] Adenosine deaminase deficiency (also called ADA deficiency or ADA-SCID) is an autosomal recessive metabolic disorder that causes immunodeficiency. […] It accounts for about 15% of all cases of severe combined immunodeficiency (SCID). […] A faulty gene inherited from both parents stops production of an essential protein called adenosine deaminase (ADA), which is particularly important for the formation of lymphocytes and a functioning immune system. […] The condition Severe Combined Immunodeficiency can occur for many reasons; one of these reasons is the deficiency of CD3 Chains.
#1 Primary Immunodeficiency Facts & Resources | CSL
https://www.csl.com/patients-public-health/rare-and-serious-diseases/immunodeficiency-and-autoimmune-diseases/primary-immunodeficiency
Primary immunodeficiency (PID) is caused by genetic factors and having a family history is the biggest risk factor for developing an immunodeficiency (PI) disorder. […] The genetic factor makes primary immunodeficiency different from secondary immunodeficiency, which is due to a medication or a disease process.
#1 Primary Immunodeficiency Diseases: Causes, Symptoms, Treatment, and More
https://www.webmd.com/children/primary-immunodeficiency
You cant catch PIDD like you can a cold or the flu. Your child has it because they were born with a broken gene that affects their immune system. […] Sometimes, this issue runs in families. Or it may have happened on its own. […] As a result, their immune system doesnt work well. In some cases, it may be totally absent. This makes your child more likely to get sick from infections that wouldnt take hold in someone else. […] If someone else in your family has a PIDD, your child is more likely to have one, too. So far, family history is the only known risk factor.
#1 Evaluation of Primary Immunodeficiency Disease in Children | AAFP
https://www.aafp.org/pubs/afp/issues/2013/0601/p773.html
One in 2,000 children younger than 18 years is thought to have a primary immunodeficiency disease. […] More than 180 primary immunodeficiency diseases have been identified, and that number is growing as advances in genetic technology allow for further identification of specific defects of immunity. […] In the United States, the most common types of primary immunodeficiency disease in children are antibody disorders, followed by combined B-cell and T-cell disorders, phagocytic defects, and complement disorders. […] Many primary immunodeficiency diseases are hereditary (most hereditary conditions are autosomal recessive inherited or X chromosomelinked). […] A child with recurrent serious infections who has a positive family history of these types of diseases or who is from an ethnicity associated with higher parental consanguinity (e.g., northern and sub-Saharan Africa; the Middle East; portions of western, central, and southern Asia) should be screened for an immunodeficiency disease.
#1 Primary Immunodeficiency (PID) – Australasian Society of Clinical Immunology and Allergy (ASCIA)
https://www.allergy.org.au/patients/immunodeficiencies/primary-immunodeficiency
Inborn errors of immunity (IEI) include primary immune deficiencies (PID) and are a group of more than 550 potentially serious chronic medical conditions, that can lead to frequent or severe infections, swellings, and autoimmune problems. […] PID/IEI disorders can be caused by defects in the genes that control the immune system and may be inherited. […] Some PID/IEI disorders may increase the chance of autoimmunity or cancer. […] PID/IEI disorders are different to AIDS (acquired immunodeficiency syndrome), that is due to human immunodeficiency virus (HIV). […] PID/IEI disorders can be categorised into the following five main groups, according to what part of the immune system is affected. […] The complement system has an important role in the control of inflammation, killing of germs and clearance of damaged cells. Some complement deficiencies can increase the risk of autoimmune disease, whilst others result in severe infections such as meningitis or septicaemia.
#1 Primary Immunodeficiency â Causes, Symptoms, and Treatments
https://csipharmacy.com/understanding-pid/
Primary Immunodeficiency conditions are caused by genetic mutations that affect the immune system. […] These mutations can interfere with the production of immune cells or proteins that are vital for defending the body against infections. […] Some mutations may result in partial immune dysfunction, while others cause complete absence or malfunction of immune cells, making individuals highly susceptible to infections.
#1
https://www.alliedacademies.org/articles/primary-immunodeficiency-disorders-genetic-causes-and-therapeutic-advances-31680.html
Primary Immunodeficiency Disorders (PIDs) are a group of rare, genetically inherited conditions that impair the immune systems ability to defend the body against infections. These disorders result from defects in the development, function, or regulation of immune cells, leading to increased susceptibility to infections, autoimmune diseases, and, in some cases, malignancies. Understanding the genetic basis of PIDs has been critical for developing targeted therapies and improving patient outcomes. […] PIDs are caused by mutations in genes responsible for the normal functioning of the immune system. These mutations can be inherited in various patterns, including autosomal dominant, autosomal recessive, and X-linked inheritance. For example, Severe Combined Immunodeficiency (SCID) often results from mutations in the IL2RG gene, affecting the gamma chain of several interleukin receptors, leading to defective T and B cell function. Similarly, mutations in the BTK gene cause X-linked agammaglobulinemia, impairing B cell development.
#1 Genetic causes of primary immunodeficiency in the Jordanian population
https://www.spandidos-publications.com/10.3892/br.2024.1848
Primary immunodeficiency disorders (PID), also termed as inborn errors of immunity (IEI), encompass a heterogeneous array of conditions characterized by compromised immune system function involving essential components, such as neutrophils, macrophages, dendritic cells (DC), complement proteins and natural killer cells, as well as T and B lymphocytes. […] While PIDs are primarily hereditary, acquired deficiencies have also been identified. It is crucial to differentiate IEI from secondary immunodeficiencies, which arise more frequently due to various factors such as infections, medications, metabolic disease and environmental conditions. By contrast, IEI stem from genetic anomalies resulting in impaired immune cell functionality. […] The advent of whole-exome sequencing (WES) has significantly contributed to identifying novel causative genes in IEI cases.
#2 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text
https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5
Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. […] Most PIDs result from inherited defects in immune system development and/or function; however, acquired forms have also been described. […] It is important to note that PIDs are distinct from secondary immunodeficiencies that may result from other causes, such as viral or bacterial infections, malnutrition, immunoglobulin (Ig) loss, malignancy or treatment with drugs that induce immunosuppression. […] The clinical presentation of PIDs is highly variable; however, most disorders involve increased susceptibility to infection. […] PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID.
#2 Primary Immunodeficiency: Types & Symptoms
https://my.clevelandclinic.org/health/diseases/17964-primary-immunodeficiency
Primary immunodeficiency refers to a group of more than 400 disorders that affect your immune system. These disorders prevent your immune system from functioning properly. This can make you more susceptible to infection and certain diseases, including autoimmune diseases and cancers. […] Genetic mutations (changes) cause primary immunodeficiency. Theyre usually inherited, or passed down, within families, but can sometimes pop up sporadically. […] Primary immunodeficiency results from genetic mutations affecting one or several components of your immune system, including cells and proteins. These mutations may cause parts of your immune system to be: Less active than usual. Defective. Totally absent. […] In 50% to 60% of cases, primary immunodeficiency relates to defects in B lymphocytes (B cells). These immune system cells make antibodies, specific proteins in your body. Your immune system uses antibodies to destroy pathogens (disease-causing agents) like bacteria or viruses. […] Genetic mutations cause most PIDD disorders, so theres no way to prevent them. If primary immunodeficiency runs in your family, you may want to consider genetic counseling.
#2 Primary Immunodeficiency Etiology and Incidence
https://www.uspharmacist.com/article/primary-immunodeficiency-etiology-and-incidence
Literature defines primary immunodeficiency as a heterogeneous group of inherited disorders characterized by defects in immune function that result in an augmented susceptibility to infections and/or immune dysregulation, including autoimmunity and malignancy. […] The IDF notes that PIDDs manifest as a result of genetic mutations that impair the immune system’s ability to function effectively, and as a result, these mutations can disrupt various components of the immune system, including B cells, T cells, phagocytes, or complement proteins. […] The majority of PIDD disorders are inherited from one or both parents, although some mutations can occur spontaneously.
#2 Primary Immunodeficiency | Boston Children’s Hospital
https://www.childrenshospital.org/conditions/primary-immunodeficiency
Primary immunodeficiency disorders (PIDDs) are a group of inherited conditions affecting the immune system, due to a lack of, or dysfunction of white blood cells, which have important roles in fighting infections. […] PIDDs are genetic disorders, meaning that every cell in the body carries the mutated gene, responsible for their PID. […] Since PIDDs are caused by genetic changes, these may be inherited. […] PIDDs are present at birth, although the symptoms may not begin until later in life, sometimes even in teenage years or adulthood. Thus, PIDDs are not caused by environmental exposures, medications, trauma, diet or events occurring during pregnancy. […] PIDDs are genetic disorders, meaning that every cell in the child’s body usually carries a defective or mutated gene that causes the disease. […] No. So far, research only shows genetics as the cause for PID.
#2 Genetic aspects of primary immunodeficiency | Great Ormond Street Hospital
https://www.gosh.nhs.uk/conditions-and-treatments/conditions-we-treat/genetic-aspects-primary-immunodeficiency/
Primary immunodeficiency disorders are the result of defects in an individuals genetic make-up. These defects are mistakes that occur in genes and are passed from generation to generation. […] In an increasing number of immunodeficiency disorders, the precise mistake in the relevant gene can now be identified in the laboratory, and this not only helps to determine the best treatment but also means that accurate counselling can be offered to the family, and screening tests can be offered in pregnancy if requested. […] There are two main types of inheritance pattern for immunodeficiency disorders: X-linked and autosomal recessive. A small number of disorders are inherited in an autosomal dominant pattern. […] Mutations on the X chromosome occur spontaneously with a relatively high frequency. This means that an X-linked disorder can occur in a family with no previous history of the disorder, and this is the case in approximately 30 per cent of newly diagnosed males.
#2
https://link.springer.com/article/10.1007/s10875-022-01289-3
Mechanisms of disease in IEI depend on the nature of the variant as well as the mode of inheritance. […] Thus, monoallelic variants can cause disease by haploinsufficiency, negative dominance, or GOF. In contrast, biallelic genetic lesions (homozygous, compound heterozygous) cause autosomal recessive (AR) traits by loss of expression, loss of function (LOF), GOF, or even neomorphic function of the encoded protein, while X-linked recessive traits arise from LOF or GOF variants on the X chromosome, either in hemizygosity in males, or homozygous state in females. […] The fact that some monogenic variants are pathogenic clearly highlights the non-redundant and fundamental roles of individual genes and proteins, and associated pathways and cell types, in the development and function of leukocytes and non-hematopoietic cells that contribute to immune homeostasis and host defense.
#2 Immunodeficiency (Primary and Secondary) | Doctor
https://patient.info/doctor/immunodeficiency-primary-and-secondary
Mostly these are inherited single-gene disorders that present in infancy or early childhood with the exception of common variable immunodeficiency which usually occurs in adults. […] Mutations/deletions of genes governing stem cell differentiation have been identified and over 250 disorders have been genetically identified with new disorders continually being described. […] Once thought to be rare, symptomatic primary immunodeficiencies are now considered to range from 1:500 to 1:500,000 in the general population in the USA and Europe. […] The age of presentation varies widely. […] 70% occur in males due to X-linked inheritance in many syndromes. […] B-cell defects account for 50% of primary immunodeficiency. […] T-cell defects account for 30%, phagocytic deficiencies 18% and complement deficiencies 2%. Knowledge about the function and diversity of B cells in health and disease has now become quite detailed but there is still much to learn.
#2 Immunodeficiency (Primary and Secondary) | Doctor
https://patient.info/doctor/immunodeficiency-primary-and-secondary
X-linked (Bruton’s agammoglobulinaemia): the agammaglobulinaemia is an X-linked immunodeficiency in which there is a failure to produce mature B-lymphocyte cells. […] Selective IgAD occurs in about 1/400 people. […] Cell-mediated immunity can be subject to a number of genetic defects affecting the function of the T cells. […] Thymic aplasia (DiGeorge syndrome): there are genetic defects of the thymus and often the parathyroid glands and heart, associated with T-cell dysfunction and significant immune deficiency. […] Severe combined immunodeficiency disease: this is in fact a group of rare congenital diseases in which there is severe and usually fatal immune deficiency. […] A wide range of inherited immunodeficiency conditions has been identified, many involving a single gene.
#2 Overview of Immunodeficiency Disorders – Immunology; Allergic Disorders – MSD Manual Professional Edition
https://www.msdmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders
Treatment and prognosis of primary immunodeficiency disorders depend on the specific disorder. […] Complement deficiencies are rare (2% of primary immunodeficiencies); they include isolated deficiencies of complement components or inhibitors and may be hereditary or acquired. The deficiencies result in defective opsonization, phagocytosis, and lysis of pathogens and in defective clearance of antigen-antibody complexes. […] The most serious consequences are Recurrent infection, which is due to defective opsonization, Autoimmune disorders (eg, systemic lupus erythematosus, glomerulonephritis), which are due to defective clearance of antigen-antibody complexes.
#3 Primary immunodeficiency | Allergy, Asthma & Clinical Immunology | Full Text
https://aacijournal.biomedcentral.com/articles/10.1186/s13223-018-0290-5
Primary immunodeficiency disorder (PID) refers to a large heterogeneous group of disorders that result from defects in immune system development and/or function. […] Most PIDs result from inherited defects in immune system development and/or function; however, acquired forms have also been described. […] It is important to note that PIDs are distinct from secondary immunodeficiencies that may result from other causes, such as viral or bacterial infections, malnutrition, immunoglobulin (Ig) loss, malignancy or treatment with drugs that induce immunosuppression. […] The clinical presentation of PIDs is highly variable; however, most disorders involve increased susceptibility to infection. […] PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID.
#3 Primary immunodeficiency | Beacon Health System
https://www.beaconhealthsystem.org/library/diseases-and-conditions/primary-immunodeficiency?content_id=CON-20376887
Many primary immunodeficiency disorders are inherited passed down from one or both parents. Problems in the genetic code that acts as a blueprint for producing the cells of the body (DNA) cause many of these immune system defects. […] There are more than 300 types of primary immunodeficiency disorders, and researchers continue to identify more. They can be broadly classified into six groups based on the part of the immune system that’s affected: B cell (antibody) deficiencies, T cell deficiencies, Combination B and T cell deficiencies, Defective phagocytes, Complement deficiencies, Unknown (idiopathic).

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