X-linked Immunodeficiencies and Complement Deficiencies

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Questions and Answers

Which disorder is associated with a deficiency in the Btk gene?

NKG2D deficiency

Wiskott Aldrich syndrome

X-linked agammaglobulinemia (correct)

Chronic granulomatous disease

Which complement deficiency is most likely to result in increased susceptibility to Neisseria infections?

C3 deficiency

C2 deficiency

C1q deficiency

C5-C9 deficiencies (correct)

What is the main characteristic of Wiskott Aldrich syndrome?

Defective macrophage function

Thrombocytopenia, eczema, and recurrent infections (correct)

Combined B and T cell immunodeficiency

X-linked hyper-IgM syndrome

Which of the following disorders is linked to the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)?

Foxp3 mutation Signup and view all the answers

Which gene is associated with Chronic Granulomatous Disease?

gp91phox Signup and view all the answers

Which mutations account for approximately 50% of Severe Combined Immunodeficiency (SCID) cases?

gC (X-linked) or JAK3 (autosomal recessive) mutations Signup and view all the answers

What test is used for in vitro assessment of T-lymphocyte function?

PHA stimulation test Signup and view all the answers

Which of the following is NOT included in the enumeration of B-lymphocytes?

Neutrophil count Signup and view all the answers

Which receptor does NOT utilize gC and JAK1/JAK3 configuration?

IL-4R Signup and view all the answers

What is the purpose of the NBT test in primary immunodeficiency diagnosis?

To assess phagocyte function Signup and view all the answers

Which of the following autoinflammatory disorders is characterized by mutations in the NLRP3 gene?

Cryopyrin-associated periodic syndrome Signup and view all the answers

What is the primary consequence of mutations in the interleukin-1 receptor antagonist?

Increased IL-1b activity Signup and view all the answers

Which of the following mutations is linked to common variable immunodeficiency (CVID)?

MHC class II Signup and view all the answers

Which T-cell receptor signaling pathway component is mutated in some patients affecting the maturation of T-cells?

ZAP70 Signup and view all the answers

Which of these is NOT classified as a primary immunodeficiency affecting B-cells?

Severe combined immunodeficiency Signup and view all the answers

What type of disorder is characterized by episodes of unprovoked inflammation, fever, and aches?

Autoinflammatory disorder Signup and view all the answers

Which syndrome has been associated with mevalonate kinase mutations?

Hyper-IgD syndrome Signup and view all the answers

Which of the following factors is primarily involved in the conversion of pro-IL-1b into active IL-1b?

Caspase-1 Signup and view all the answers

Mutations affecting which of these proteins would most likely cause a deficiency in T-cell responses?

IL-2Rα Signup and view all the answers

Which immune disorder specifically involves mutations leading to low levels of IgG, IgA, and/or IgM?

Common variable immunodeficiency Signup and view all the answers

In X-Linked Agammaglobulinemia, which gene is primarily associated with the developmental defect at the pre-B-cell stage?

Btk Signup and view all the answers

Which immunodeficiency is characterized by recurrent infections from Pneumocystis jirovecii and Toxoplasma?

Hyper-IgM syndrome Signup and view all the answers

What is the consequence of mutations in the TBX1 gene in DiGeorge syndrome?

Inability of the thymus to develop Signup and view all the answers

What is a common feature of Hyper-IgE syndrome regarding immunological responses?

Dysregulated IgE responses Signup and view all the answers

Which of the following descriptions best fits Selective IgA Deficiency?

Other classes of antibody compensate for IgA deficiency Signup and view all the answers

In the context of B-cell receptor signaling, which gene mutation is associated with X-Linked Agammaglobulinemia?

Btk Signup and view all the answers

Which condition is associated with very low or absent levels of IgG, IgA, and IgE?

Hyper-IgM Syndrome Signup and view all the answers

Which syndrome is particularly indicated by multiple encapsulated extracellular bacterial infections due to defective humoral immunity?

Wiskott Aldrich syndrome Signup and view all the answers

Which mechanism underlies the immune dysregulation in Hyper-IgE Syndrome?

Increased eosinophil maturation and activation Signup and view all the answers

Which factor is commonly linked to MHC class II deficiency and associated bronchopulmonary infections?

CIITA Signup and view all the answers

What is a characteristic feature of Wiskott-Aldrich Syndrome?

Defective chemotaxis of T-cells Signup and view all the answers

Which of the following mutations is primarily associated with MHC Class I Deficiency?

Mutations in TAP1, TAP2, or Tapasin Signup and view all the answers

What is the result of CIITA mutations in MHC Class II Deficiency?

Impaired positive selection of CD4+ T-cells Signup and view all the answers

What condition is characterized by unregulated T-cell activity due to Foxp3 mutations?

IPEX syndrome Signup and view all the answers

Which immunodeficiency syndrome is associated with severe defects in both cellular and humoral immunity?

Severe Combined Immunodeficiency (SCID) Signup and view all the answers

What type of infections are most commonly associated with MHC Class II Deficiency?

Chronic viral infections Signup and view all the answers

Which genetic defects account for approximately 50% of SCID cases?

gC or JAK3 mutations Signup and view all the answers

What physiological process does WASP activation facilitate during T-cell activation?

Formation of the immunological synapse Signup and view all the answers

What is the implication of Fas or Fas ligand mutations in autoimmune lymphoproliferative syndrome (ALPS)?

Defective lymphocyte apoptosis Signup and view all the answers

Which aspect of T-cell activity is primarily affected in patients with DiGeorge syndrome?

Antibody responses Signup and view all the answers

Study Notes

X-linked Primary Immunodeficiencies

Several genes located on the X chromosome are associated with primary immunodeficiencies.
PIG-A is linked to Paroxysmal Nocturnal Hemoglobinuria (PNH)
gp91phox is linked to Chronic Granulomatous Disease (CGD)
WASP is linked to Wiskott-Aldrich syndrome
Foxp3 is linked to Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome (IPEX)
gc is linked to X-linked Severe Combined Immunodeficiency (XSCID)
MAGT1 is linked to NKG2D deficiency
Btk is linked to X-linked Agammaglobulinemia (XLA)
SH2D1A is linked to X-linked Lymphoproliferative disease type 1 (XLP1)
XIAP is linked to X-linked Lymphoproliferative disease type 2 (XLP2)
CD40L is linked to X-linked Hyper-IgM syndrome
NEMO is linked to X-linked Hyper-IgM syndrome

Complement Deficiencies

Deficiencies in complement components can lead to impaired clearance of immune complexes and increased susceptibility to infections.
Deficiencies in C1q, C1r, C1s, C2, C3, C4, Factor I can lead to systemic lupus erythematosus.
Deficiencies in C5, C6, C7, C8, C9, Factor D, and properdin can lead to disseminated Neisseria gonorrhoeae and N. meningitidis infections.

Autoinflammatory Disorders

Over 30 autoinflammatory disorders exist, some with monogenic causes, others polygenic.
These disorders are characterized by episodes of unprovoked inflammation, including fever, rashes, joint/muscle aches, and abdominal/chest pain.
Dysregulation of pro-inflammatory cytokines is a hallmark of autoinflammatory disorders.
Familial Mediterranean fever is caused by mutations in the pyrin gene, a regulator of inflammasomes.
Cryopyrin-associated periodic syndrome (CAPS) is caused by NLRP3 mutations, a component of the inflammasome.
Deficiency of the interleukin-1 receptor antagonist (DIRA) is caused by IL-1 receptor antagonist (IL-1RA) mutations.
TNF receptor-associated periodic syndrome (TRAPS) is caused by p55 TNF receptor mutations.
Hyper-IgD syndrome (HIDS), also known as hyperimmunoglobulinemia D with periodic fever syndrome, is caused by mevalonate kinase mutations.

Mutations Affecting T-cell Maturation

Mutations in several genes can affect T-cell maturation.
Genes involved in T-cell development include: CLP, γC, IL-7Rα, IL-2Rα, JAK3, ADA, PNP, RAG1, RAG2, ARTEMIS, CERNUNNOS, DNA ligase 4, DNAPKcs, CD45, CD3, LCK, UNC119, CORONIN 1A, ORAI, STIM-1, ZAP70, TAP1, TAP2, TAPASIN, MST1, RHOH.

Mutations Affecting B-cell Maturation

Mutations in several genes can affect B-cell maturation.
Genes involved in B-cell development include: CLP, ADA, PNP, RAG1, RAG2, ARTEMIS, CERNUNNOS, DNA ligase 4, DNAPKcs, BTK, PI3K, p85α, λ5, Igα, Igµ chain, BLNK, LRRC8.

Examples of Primary Immunodeficiency Affecting B-cells

Common Variable Immunodeficiency (CVID) is characterized by low IgG, IgA, and/or IgM levels.
X-linked Agammaglobulinemia (XLA) is caused by mutations in the Btk gene, leading to a developmental defect at the pre-B-cell stage.
Selective IgA Deficiency is characterized by low levels of both circulating IgA and secretory dimeric IgA.

Examples of Immunodeficiencies Affecting T-cells

Several genetic defects can lead to T-cell immunodeficiencies, resulting in susceptibility to diverse infections.
Hyper-IgM syndrome is characterized by elevated serum IgM and IgD levels, but reduced IgG, IgA, and IgE levels.
Hyper-IgE syndrome is characterized by elevated serum IgE levels, recurrent infections, and an increased susceptibility to skin and lung infections.
DiGeorge syndrome is caused by mutations in the TBX1 transcription factor, resulting in thymus developmental defects.
Wiskott-Aldrich syndrome is caused by mutations in the WASp gene, affecting T-cell motility and phagocyte function.
MHC class I deficiency is caused by mutations in TAP1, TAP2, or Tapasin, leading to defective antigen presentation.
MHC class II deficiency is caused by mutations in CIITA, affecting the expression of MHC class II molecules and impairing positive selection of CD4+ T-cells.

Primary Immunodeficiencies Associated with Autoimmune Disease

IPEX syndrome is caused by mutations in the Foxp3 gene, resulting in uncontrolled T-cell activity and multisystemic autoimmune disease.
Autoimmune polyendocrine syndrome-1 (APS-1) is caused by AIRE mutations, leading to defective central tolerance of T-cells.
Autoimmune lymphoproliferative syndrome (ALPS) is caused by Fas (CD95) or fas ligand (CD95L) mutations, leading to defective lymphocyte apoptosis.

Severe Combined Immunodeficiency (SCID)

SCID is characterized by a complete failure of T-cell development, leading to severe defects in both cellular and humoral immunity.
SCID is caused by mutations in various genes affecting cytokine signaling, TCR signaling, or VDJ recombination.
Without treatment, SCID is fatal within the first year of life.
SCID phenotypes vary based on the genetic defect:
- T-B+NK-: gC, JAK3, RAG-1, RAG-2, Artemis, DNA ligase IV, Cernunnos, DNA PKcs
- T-B-NK+: IL-7Rα, CD3d, CD3e, CD3z, Coronin-1A, ZAP-70, CD45
- T-B+NK+: ADA, AK2

Diagnosis of Primary Immunodeficiency

Various tests are used to diagnose primary immunodeficiency.
T-lymphocyte enumeration involves counting CD3+ lymphocytes and their subtypes (CD4+ and CD8+).
B-lymphocyte enumeration involves counting CD20+ lymphocytes and measuring immunoglobulin levels.
Phagocyte enumeration involves determining neutrophil count.
Complement assessment involves performing a hemolysis assay.
In vitro functionality assessment of T-lymphocytes involves evaluating their response to stimulation with PHA or antigens.
In vivo functionality assessment of T-lymphocytes involves testing for delayed hypersensitivity reactions.
In vivo functionality assessment of B-lymphocytes involves measuring specific antibody levels.
Phagocyte functionality assessment involves the nitroblue tetrazolium (NBT) test.

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Description

This quiz covers key genetic links associated with X-linked primary immunodeficiencies and complement deficiencies. By exploring various genes and their corresponding immunological disorders, you will deepen your understanding of these critical components in immune system function. Test your knowledge on how these deficiencies affect health and immunity.