PID

The term "primary immunodeficiencies" (synonym: PID/immunodeficiency syndromes) covers numerous congenital (>300 entities) diseases of the immune system, which are characterized by a passive or irreversible disturbance of the immune function. Primary diseases (PID) are those in which immunodeficiency is congenital, familial and/or inherited. The PID group is contrasted with diseases and referred to by the generic term "secondary immunodeficiencies" in which the immunodeficiency is acquired. The best-known example of this is AIDS (acquired immune deficiency syndrome).

The immunodeficiencies in which the antibody deficiency is in the foreground (reduction of all immunoglobulin isotypes with severely reduced or absent B cells) account for the largest proportion of PGDs (see Primary immunodeficiencies/classification below). Here, at least two immunoglobulin major classes or one major and one IgG subclass are decreased. Examples of such immunodeficiencies are the group of variable humoral immunodeficiencies (= CVID, common variable immunodeficiency), the different variants of agammaglobulinemias, which are triggered by different mutations in the proteins that form the BCR receptor complex, the relatively frequent selective IgA deficiency (see also CVID), or the hyper IgM syndrome. In the latter, IgM is elevated or normal, IgG as well as IgA is decreased.

Diseases of the CVID group are the most frequent PIDs with antibody deficiency. It leads to recurrent respiratory tract infections often with encapsulated bacteria.

The therapy of patients with antibody deficiency should follow the interdisciplinary AWMF therapy guideline and is generally reserved for specialized centers. It essentially includes infection prophylaxis and the administration of immunoglobulins. Otherwise, the chronic disease carries a high risk of morbidity (e.g. bronchiectasis or colitis).

Specifically, this PID group can be subdivided as follows:

• X-linked agammaglobulinemia (also called agammaglobulinemia type Bruton): Mutations in the BTK gene. BTK is normally activated after crosslinking of the BZR: Severe bacterial infections. Reduction of all Ig isotypes with decreased or absent B cells. Maturation arrest of pre-B cells to mature CD19+ B cells. B-cells<2%. Most common form:>90%. No tonsils.
• IGHM defect( μ- heavy chain deficiency): Mutations in the μ-weight chain (encoded by IGHM gene), an essential component of the pre-BZR (severe bacterial infections. Number of pro-B cells normal).
• λ5 deficiency: mutations in λ5, surrogate light chain in the pre-BZR (severe bacterial infections. Number of pro-B cells normal).
• CD79A (Igα) deficiency: mutations in CD79A gene. The encoded protein is part of the pre-BZR/mutations in CD79A lead to severe bacterial infections. Number of pro-B cells normal(Autosomal recessive agammaglobulinemia 3) . Evidence of signs of dermatomyositis as well.
• CD79B (Igβ) deficiency: mutation in CD79B gene. The encoded protein is part of the pre-BCR receptor complex. CD79 mutation leads to the clinical picture of agammaglobulinemia, mutation in CD79B (severe bacterial infections, normal number of pro-B cells).
• BLNK (B cell linker protein) deficiency: mutations in BLNK gene, a scaffolding protein that binds to BTK leads to agammaglobulinemia 4 (autosomal recessive), mutation in BLNK: severe bacterial infections, normal number of pro-B cells.
• PIK3CD LOF defect (phosphatidylinositol 3-kinase, regulatory subunit): LOF mutation in the PIK3CD gene, a kinase with importance in numerous cell types(immunodeficiency 14A/ all isotypes decreased/ severe bacterial infections, autoimmunity (CED)/ decreased or absent Pro-B cells).
• p85 defect: absence of p85α chain blocks entire B cell development (severe bacterial infections. Pro B cells decreased of absent).
• Defect of transcription factor E47: Mutation in TCF3, necessary for B cell development (severe bacterial infections, failure to thrive).
• SLC39A7 (ZIP7) defect: mutation in SLC39A7 gene (clinical: agammaglobulinemia 9: early manifest infections, vesicular dermatosis, failure to thrive, thrombocytopenia)
• TOP2B defect (Hoffman syndrome): Mutation in TOP2B (recurrent infections, facial dysmorphia, limb abnormalities).

Immunodeficiencies in which antibody deficiency is predominant/ marked reduction of at least 2 Ig isotypes (IgG and IgA) B-cell count normal or decreased

• CVID (CVID stands for "common variable immunodefiency", also called "late onset hypogammaglobulinemia"): unknown genetic defect; IgG and IgA decreased, IgM may be normal; 10% of patients have pos. family history (infections, autoimmune cytopenias, granulomatous and polyclonal lymphoproliferative complications.
• Activated PI3K-δ (phosphatidylinositol-4,5-bisphosphate 3-kinase) syndrome, APDS1: GOF mutation at PIK3CD, encodes p110d subunit of PI3K (IgG2 deficiency, reduced Ak formation against polysaccharides; respiratory infections, bronchiectasis, chronic EBV and CMV infections, autoimmunity, lymphoproliferation, lymphoma. Transitional B cells )
• PIK3R1 defect (PI3KR1 stands for phosphoinositide 3-kinase regulatory subunit 1): Activating LOF mutation in the PIK3R1 gene/ The PIK3R1 gene encodes the p85α subunit of PI3K/ clinical(agammaglobulinemia 7): IgA deficiency, low IgG, hyper IgM possible (growth retardation, chronic EBV and CMV infections, lymphoproliferation, lymphoma. Transitional B cells increased).
• PTEN defect: (LOF) mutation in PTENgene lead to a known tumor suppressor gene, have increased risk of multiple benign and malignant tumors, e.g. breast, thyroid, endometrial and colon cancer. This is called PTEN hamartomous tumor syndrome (PHTS). PHTS patients may also be at increased risk for immunological dysregulations such as autoimmunity and immunodeficiencies. In addition, a decreased ability of dendritic cells to activate CD8+ T cells may be observed, leading to impaired tumor defense. Immunodeficiencies in PHTS patients have not been extensively studied but may be a manageable factor contributing to the increased risk of cancer in PHTS.
• CD19 deficiency: Mutations in CD19 deficiency leads to variable immunodeficiency syndrome(CVID3; see also CVID): Mutations in the CD19 gene, a transmembrane protein for amplification of BZR signaling leads to decreased IgG and IgA; IgM may be normal (recurrent infections, glomerulonephritis possible; no autoimmune phenomena).
• CD81 deficiency: CD81, together with CLDN1, acts as a co-receptor for hepatitis C virus (HCV) in hepatocytes/ together with CLDN1, forms a CLDN1-CD81 receptor complex that is essential for HCV to enter the host cell. Mutations in the CD81 gene lead to immunodeficiency syndrome (Common Variable Immunodeficiency 6/CVID6,mutation in CD81). IgG and are IgA decreased, IgM may be normal. (Recurrent infections, IgA glomerulonephritis with leukocytoclastic vasculitis are possible/ absence of CD81 prevents expression of CD19).
• CD20 deficiency: mutations in MS4A1 gene, a surface protein for B cell and plasma cell development. IgG is decreased, other immunoglobulins are variably altered (recurrent infections). Mutation leads to CVID5.
• CD21 Deficiency: Mutations in CD21 (= complement receptor 2, CR2), complexed with CD19. IgG decreased, poor polysaccharide response (Recurrent infections; CD2 is the receptor for EBV).
• TACI defect: mutations in the TNFRSF13B gene. The encoded TACI protein belongs to the TNFR family/is present on B cells/receptor for BAFF and APRIL; TACI mutations are associated with immunodeficiency in humans, as a significant proportion of CVID patients have TACI mutations. People with this disorder produce abnormally low levels of antibodies needed to protect against infection. Monoallelic variants result in variable clinical expression of the syndrome. Selective IgA deficiency type 2 is induced by mutation in the TNFRSF13B gene.
• BAFF receptor defect: mutation in the TNFRSF13C gene (BAFF-R/BAFF receptor). BAFF-R belongs to TNFR family/mutation leads to low IgG and IgM/clinicalCVID4.
• TWEAK defect: mutations in TWEAK (TNFSF12). Low IgM and IgA, no polysaccharide ac. (Bacterial infections, pneumonias, verrucae vulgares, neutropenia, thrombocytopenia).
• TRNT1 defect: (TRNT1 stands for tRNA nucleotidyl transferase, CCA-adding, 1)Mutations in the TRNT1 gene lead to SIFD (sideroblastic anemia with immunodeficiency, fevers and developmental delay) with hypogammaglobulinemia, B-cell deficiency, congenital sideroblastic anemia, deafness, developmental delay.
• NFKB1 defect (NFKB1 stands for nuclear factor of kappa light polypeptide gene enhancer in B-cells 1): Mutation in NFKB1 gene leads to complex immunodeficiency syndrome/ B-cells normal or decreased (recurrent sinopulmonary infections, COPD, EBV proliferation, autoimmune cytopenias, alopecia and autoimmune thyroiditis).
• NFKB2 defect (NFKB2 stands for nuclear factor of kappa light polypeptide gene enhancer in B-cells 2): Mutations in the NFKB2 gene, which belongs to the non-classical NFkB signaling pathway. All isotypes decreased, partial low B-cells/recurrent infections, alopecia, endocrinopathies such as NNR insufficiency or ACTH deficiency.
• IKAROS defect (IKAROS is synonymous with IKZF1. IKZF1 stands for Zinc Finger Protein, Subfamily 1A) Mutation in IKZF1 gene induce a CVID phenotype: B cells decreased (Recurrent sinopulmonary infections, increased ALL risk).
• IRF2BP2 defect (IRF2BP2 stands for interferon regulatory factor 2-binding protein 2): Autosomal dominant mutation in the IRF2BP2 gene (recurrent infections, autoimmunity and autoinflammation possible).
• ATP6AP1 defect (ATP6AP1 stands for "ATPase H+ Transporting Accessory Protein 1: an X-linked recessive mutation in the ATP6AP1 gene leads to variable immunological findings; furthermore hepatopathy, leucopenia, low serum copper levels)
• ARHGEF1 defect (ARHGEF1 stands for" Rho Guanine Nucleotide Exchange Factor 1"): Autosomal recessive mutations in the ARHGEF1 gene result in decreased Ig, decreased antibody formation, recurrent infections, bronchiectasis.
• SH3KBP1 (CIN85) defect (SH3KBP1 stands for "SH3 Domain Containing Kinase Binding Protein1"): X-linked recessive mutations in the SH3KBP1 gene lead to decreased IgG and IgM, reduced antibody formation, severe bacterial infections.
• SEC61A1 defect (SEC61A1 stands for "SEC61 Translocon Subunit Alpha 1"): Autosomal dominant mutations in the SEC61A1 gene result in decreased Igs as well as severe recurrent respiratory infections.
• RAC2 defect (RAC2 stands for "Rac Family Small GTPase"): Autotosomal recessive mutations in the RAC2 gene result in decreased all Igs; reduced vaccine response. B cells are normal or decreased; furthermore recurrent respiratory infections, poststreptococcal glomerulonephritis, urticaria.
• MOGS defect (MOGS stands for "mannosyl-oligosaccharide glucosidase"): autosomal recessive mutations in the MOGS (GCS1) gene lead to severe hypogammaglobulinemia, bacterial and viral infections; furthermore severe neurological deficits. Corresponds to CDG-IIb .

Immunodeficiencies in which antibody deficiency is predominant/ Decreased IgG and IgA with normal or increased IgM with normal number of B cells.

• AID Deficiency (AID stands for "Activation induced Cytidine deaminase") Mutations in the AICDA gene; IgG and IgA decreased, IgM increased, Memory B cells normal but without somatic hypermutation (SHM) AR Bacterial infections, enlarged lymph nodes and germinal centers, autoimmunity.
• AID deficiency (AID stands for "Activation induced Cytidine deaminase"): autosomal domian mutations in the AICDA gene lead to decreased IgG and IgA ; IgM increased; memory B cells and somatic hypermutation normal; furthermore bacterial infections, enlarged lymph nodes and germinal centers
• UNG deficiency (UNG stands for uracil N-glycosylase): autosomal recessive mutations in the UNG gene lead to decreased IgG and IgA, increased IgM; still enlarged lymph nodes and germinal centers
• INO80 defect (INO80 stands for INO80 complex subunit): Mutation in INO80, necessary for chromatin remodeling: IgG and IgA decreased, IgM increased; still severe bacterial infections.
• MSH6 defect: (MSH6 stands for "mutS homolog 6"): autosomal recessive mutation in the MSH6 gene leads to a DNA repair defect; IgG and IgA variable, IgM elevated; furthermore, low-switched memory B cells, disruption of SHM and CSR; caveat: cancer risk increased

Isotype or light chain deficiency with normal B cells.

• Immunoglobulin heavy chain defect; autosomal recessive mutation or chromosomal defect at 14q32; IgG1 or IgG2 ↓, IgG4 absent, in some cases IgE and IgA1 or IgA2 absent; sometimes asymptomatic course.
• κ-chain (IGKC) defect autosomal recessive mutations in the constant kappa gene IGKC; all immunoglobulins have the λ-chain; clinically asymptomatic.
• IgG subclass defects; gene defect unknown; reduction of one or more subclasses; clinically usually asymptomatic! Minority with recurrent infections. Some with poor specific antibody production.
• IgA plus IgG subclass deficiency; gene defect unknown; decrease in IgA and one or more subclasses. Mostly recurrent bacterial infections.
• Specific antibody deficiency: gene defect unknown; Ig and B cells normal; impaired formation of certain e.g. polysaccharide-specific antibodies
• Selective IgA deficiency: Very few with TACI mutation: IgA severely decreased or absent. Mostly asymptomatic. Partial poor response to polysaccharide Ag. Some develop into CVID, others are familially coexistent with it
• Transient hypogammaglobulinemia of infancy; differentiation defect: delayed maturation of helper cell function; IgG and IgA decreased; clinically usually asymptomatic, normal ability to produce specific antibodies
• CARD11 (caspase recruitment domain) defect, autosoma dominant GOF mutation in CARD11 gene. Leads to persistent NFkB activation Congenital B-cell lymphocytosis. Decreased antibody formation, lymphadenopathy, splenomegaly.
• Selective IgM deficiency; unknown gene defect/ clinical: bacterial infections, e.g. pneumococci.