PID

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

Immune dysregulation can be a significant indicator for the presence of PID. Associated autoimmune phenomena, e.g. autoimmune-mediated cytopenias or thyroid dysfunctions, are regularly observed in PID. Slow progressive lymphoproliferation, splenomegaly or lymph node swelling or acute phases of hemophagocytic lymphohistiocytosis may thus be an expression of congenital regulatory disorder. Therapy, depending on the clinic, includes wait-and-see approach up to administration of strong immunosuppressive therapy or stem cell transplantation.

Of particular interest is a group of immune dysregulations with susceptibility to EBV. Affected are 10 genes whose mutations cause deficiencies of T cells. The consequence is persistent EBV infections often combined with benign lymphoproliferation and an eminent risk for the development of EBV-associated B-cell lymphoma. Occasionally, photosensitivity(CARMIL2 defect), signs of atopy or SLE-like autoimmunology(PRKCD defect) occur.

Familial hemophagocytic lymphohistiocytoses (FHL)

FHL without hypopigmentation

• PRF1 defect: AR/mutations in PRF1 (perforin) gene are associated with familial hemophagocytic lymphohistiocytosis 2. Perforin is important cytolytic protein. Severe inflammatory states with fever, macrophage activation, pancytopenia, hepatosplenomegaly, decreased NK and CTL activities, T cells activated.
• UNC13-D (unc-13 homolog D, Munc 13-4) defect: AR/FHL3 mutations in the UNC13D gene are associated with familial hemophagocytic lymphohistiocytosis 3. The encoded protein require vesicles to fuse/severe inflammatory states with fever, macrophage activation, pancytopenia, hepatosplenomegaly, decreased NK and CTL activities, T cells activated.
• STX11 defect: AR/ AR/mutation in STX11 gene/ encoded protein = syntaxin, is necessary for fusion of secretory vesicles with target membrane/mutations of the gene are associated with familial hemophagocytic lymphohistiocytosis 4/ severe inflammatory states with fever, macrophage activation, pancytopenia, hepatosplenomegaly, decreased NK and CTL activities, T cells activated.
• STXBP2 (syntaxin binding protein 2, = Munc 18-2) defect: AR or AD/FHL5 mutations in STXBP2 , necessary for fusion of secretory vesicles with target membrane/mutations of the gene are associated with familial hemophagocytic lymphohistiocytosis 5/ severe inflammatory conditions with fever, macrophage activation, pancytopenia, hepatosplenomegaly, decreased NK and CTL activities, T cells activated.
• FAAP24 defect: AR/ mutation in FAAP24 gene. Autologous EBV-transformed B cells cannot be killed /EBV-induced lymphoproliferation. T cells are activated, NK function normal.
• SLC7A7 defect: AR/ mutation in SLC7A7 gene, leads to hyperinflammatory function of macrophages/ to the clinical picture of "Lysinuric protein intolerance" with vomiting, diarrhea, failure to thrive, hepato-splenomegaly, abnormalities of bone marrow, bleeding tendency, alveolar proteinosis).

Familial hemophagocytic lymphohistiocytosis with hypopigmentation.

• Chediak-Higashi syndrome: AR/defect in LYST gene/disrupted lysosomal transport/partial albinism, hepatosplenomegaly, HLH, low NK and CTL activities (cytotoxicity and degranulation); severely enlarged lysosomes, encephalopathic accelerated phase.
• Griscelli syndrome type 2: AR/defect in RAB27A- gene/encodes for GTPase for docking of secretory vesicles to cell membrane/partial albinism; fever, HLH; low NK and CTL activities (cytotoxicity and degranulation)
• Hermansky-Pudlak syndrome type 2: AR/mutations in AP3B1 gene/encodes for ß-subunit in AP-3 complex/partial albinism, recurrent infections, pulmonary fibrosis, bleeding tendency, HLH, neutropenia, decreased NK cells and CTL (cytotoxicity and degranulation)
• Hermansky-Pudlak syndrome type 10: AR/ mutations in AP3D1 gene/partial albinism, recurrent infections, neutropenia, hearing loss, convulsions, developmental delay.

Diseases associated with immune dysregulation/ Genetic defects of regulatory T cells.

• IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked): XL/defect in FOXp3, a transcription factor for regulatory T cells/ autoimmune enteropathy, early diabetes, thyroiditis, hemolytic anemia, thrombocytopenia, atopic dermatitis/ deficiency of FOXp3-pos. CD4+/CD25+ cells, IgA and IgE elevated.
• IPEX-like: AR/CD25 deficiency due to mutation in IL2RA gene/defect of IL-2Rα chain(CD25)/disease pattern of immunodeficiency 41 with lymphoproliferation and autoimmunity with recurrent viral, fungal and bacterial infections, lymphadenopathy and variable autoimmune features such as autoimmune enteropathy and atopic dermatitis.
• IL2RB (CD122) defect:AR/mutation in the IL2RB gene/encodes the beta chain of the IL2 receptor/disrupted signaling on interleukin-2/interleukin-15/memory B and T cells ↑, Tregs ↓/lymphoproliferation, lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, atopic dermatitis, enteropathy, hypergammaglobulinemia, recurrent viral (EBV, CMV) infections.
• CTLA4 (Cytotoxic T-lymphocyte antigen 4) haploinsufficiency (= ALPS-V): AD/ mutation in the CTLA4 gene. The protein inhibits T-cell activation/mutations of the gene are associated with: autoimmune cytopenias, lymphocytic enteropathy, interstitial lung disease as well as with lymphoid infiltrates in non-lymphoid organs, tendency to infection.
• LRBA (lipopolysaccharide responsive beige-like anchor protein) defect: AR/ mutation in LRBA gene/ CD4 and B cells decreased. T-cell dysregulation/ hypogammaglobulinemia especially with IgG and IgA /recurrent infections, inflammatory bowel disease, autoimmunity, EBV infections (see belowVariable immunodeficiency syndrome 8 with autoimmunity and mutations in LRBA gene).
• DEF6 defect: AR/ mutation in DEF6 gene, mild lymphopenia, functional disorder of Tregs/ enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections(Immunodeficiency-87 with autoimmunity).
• STAT3 GOF defect (clinical: hyper IgE syndrome1): AD/ GOF mutation in STAT3 gene /recurrent infections, IL17 deficiency, IgE-high, eosinophilia, lymphoproliferation, organ related autoimmunity. B- and T-cells incl. Tregs decreased.
• BACH2 defect: AD/mutation in BACH2, haplinsufficiency in a major transcription factor. Progessive T lymphopenia, impaired memory B cells/lymphocytic colitis, sinopulmonary infections .
• FERMT1 defect: AR/ mutation in FERMT1. Mutation is associated with the fourth distinct form of hereditary epidermolysis bullosa. Very rare poikilodermic clinical picture with "variable " blistering/B and T cells normal, but intracellular accumulation of IgG, IgM, IgA and C3 in colloid bodies under the basement membrane/further: skin atrophy, photosensitivity, skin fragility and peeling.

Diseases associated with immune dysregulation/ autoimmunity with or without lymphoproliferation

• APECED defect (APECED stands for "autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy" = APS-1): autosomal recessive or autosomal dominant defect in the AIRE gene, a transcription factor; this is necessary for formation of "self" tolerance in the thymus. Clinically, autoimmune diseases of parathyroid glands, adrenal glands and other endocrine organs are found; furthermore, candidiasis, enamel hypoplasia, alopecia areata, pernicious anemia, enteropathy.
• ITCH defect (ITCH stands for itchy E3 ubiquitin protein ligase): autosomal recessive mutations in the ITCH gene lead to a defective E3 ubiquitin ligase (transfers ubiquitin to signaling molecules) incl. PLCγ1 (see below ITCH E3 ubiquitin ligase deficiency). The molecular defect prevents induction of anergy in autoreactive T cells, Tregs diminished/continued: multi-organ autoimmunity with thyroiditis, type 1 diabetes, early manifest chronic interstitial lung disease, failure to thrive, enteropathy, developmental delay, facial dysmorphia.
• Tripeptidyl peptidase II defect: autosomal recessive mutation in the TPP2 gene encoding a serine exopeptidase/the mutation results in disruption of extralysosomal peptide degradation. Clinical: severe autoimmune cytopenias, variable lymphoproliferation, hypergammaglobulinemia, propensity to infection. Decreased B and T cells, immune dysregulation, premature immune senescence(immunodeficiency 78 with autoimmunity, developmental defects and mutations in TPP2 gene).
• JAK1-GOF defect (JAK1 stands for Janus kinase 1): autosomal recessive mutations in the JAK1 gene lead to eosinophilia, eosinophilic enteritis, growth retardation and viral infections.
• Prolidase deficiency: autosomal recessive mutations in the PEPD gene which is located on chromosome 19q13.11. PEPD stands for peptidase D. Mutations lead to prolidase deficiency. Clinical: frequent formation of autoantibodies, chronic ulcers of the skin, eczema, tendency to infections such as bacterial vaginosis.

Diseases in immune dysregulation/ immune dysregulation with colitis.

• IL10 defect: autosomal recessive mutation in the IL10 gene. The gene defect leads to impaired secretion of interleukin-10. Clinical: interleukin-10 deficiency leads to inflammatory bowel disease, folliculitis, recurrent respiratory infections, arthritis.
• IL10Ralpha defect: AR/mutations in IL10RA. No response via IL10 family receptors/chronic inflammatory bowel disease, folliculitis, recurrent respiratory infections, arthritis, lymphoma.
• IL10Rbeta defect: AR/mutations in IL10RB. No response via IL10 family receptors/ inflammatory bowel disease, folliculitis, recurrent respiratory infections, arthritis, lymphoma.
• NFAT5 (Nuclear Factor of Activated T-cells) haploinsufficiency: AD/mutations in NFAT5. Decreased memory B-cells and plasmablasts/ inflammatory bowel disease, recurrent respiratory infections.
• TGFB1 defect: AR/mutation in TGFB1 gene. T cell proliferation to anti-CD3 ↓/chronic inflammatory bowel disease, recurrent viral infections, microcephaly, encephalopathy .
• RIPK1 defect: AR/ mutation iin the RIPK1 gene/dysfunctional activation of MAPK and NFkB signaling pathways/recurrent infections, early-onset inflammatory bowel disease, progressive polyarthritis (see also immunodeficiency 57 with autoinflammation).

Diseases with immune dysregulation/ALPS =Autoimmune lymphoproliferative syndromes (Canale Smith syndrome). Diseases are only partially considered as "immunodeficiency

• ALPS-FAS/ CD95 deficiency: autosomal dominant or autosomal recessive mutations in the TNFRSF6B gene(TNFRSF6B stands for "TNF Receptor Superfamily Member 6B") on chromosome 20q13.33. The mutations affect the apoptosis receptor CD95/Fas. Clinically, the mutation leads to a severe clinical picture with adenopathy, splenomegaly, autoimmune cytopenias, impaired apoptosis. Cave: increased risk of lymphoma. Double-negative T cells (CD4-/CD8-) increased, IgG and IgA normal or elevated, elevation of sFasL, IL-10 and vitamin B12.
• ALPS-FASLG deficiency: autosomal recessive mutations in the FASLG gene located on chromosome 1q24.3 (FASLG stands forFas ligand, the ligand for the apoptosis receptor CD95. Clinical: Adenopathy, splenomegaly, autoimmunity (autoimmune lymphoproliferative syndrome - ALPS), systemic lupus erythematosus, impaired apoptosis. Double-negative T cells increased; FasL not increased.
• ALPS caspase 10, caspase (caspase stands for cysteinyl aspartate proteases) 10 defect: AD/mutations in CASP10 gene located on chromosome 2q33.1/ the encoded protein, caspase 10 is involved in apoptotic signaling pathway. Clinical: Adenopathy, splenomegaly, autoimmunity, impaired apoptosis. Double-negative T cells increased.
• ALPS caspase 8, caspase 8 defect(caspase stands for: cysteinyl aspartate proteases): AR/ mutations in CASP8 (involved in apoptotic and activation signaling pathway) lead to recurrent bacterial and viral infections, lymphadenopathy, splenomegaly, impaired lymphocyte apoptosis, hypogammaglobulinemia. Only low proliferation of double-negative T cells.
• FADD defect (FADD stands for "Fas Associated Via Death Domain): autosomal recessive mutations in the FADD gene which is located on chromosome 11q13.3, leads to a defect of the "FAS associated adapter molecule" encoded by this gene. Clinical: Recurrent bacterial and viral infections, functional hyposplenia, episodes of encephalopathy and hepaticdysfunction(see belowImmunodeficiency 90 with encephalopathy, functional hyposplenia and hepatic dysfunction) .

Diseases associated with immune dysregulation/immune dysregulation with susceptibility to EBV/lymphoproliferation.

• SH2D1A (SH2D1A stands for "SRC homology domain 2" or "SLAM-associated protein (SAP) defect (XLP1)". X-linked recessive mutations in the SH2D1A gene (chromosome Xq25) an adaptor protein that regulates intracellular signaling. Clinical: Clinical and immunological manifestations triggered by EBV infection, HLH, lymphoproliferation, aplastic anemia, lymphoma, hypogammaglobulinemia. Absence of iNKT cells, reduced NK and CTL activity.
• XIAP (XIAP stands for "X-linked inhibitor of apoptosis") defect: defect in the XIAP gene located on chromosome Xq25, an inhibitor of apoptotic cell death. Increased susceptibility of T cells to apoptosis. Clinical and immunological manifestations triggered by EBV infection; splenomegaly, hepatitis; aplastic anemia, lymphoma, hemophagocytosis, colitis, IBD, pyoderma of the skin. Low iNKT cells (see below Lymphoproliferative Syndrome, X-Linked).
• CD27 defect: autosomal recessive defect in the CD27 gene. The encoded protein CD27 is a member of the TNF-R superfamily (TNFRSF7). CD27 is necessary for the generation and maintenance of T cell immunity. Clinical: EBV-induced hypogammaglobulinemia and symptoms: HLH. Aplastic anemia, lymphoma. No memory B cells. Decreased antibody production; low iNKT cells.
• CD70 defect: autosomal recessive mutation in the CD70 gene. The defectively encoded CD70 protein leads to T and B cell dysfunction with low Tregs; decreased Ig; reduced vaccine responses; further to EBV susceptibility. Cave: increased risk for Hodgkin's disease. Some patients react with autoimmunity (see Lymphoproliferative syndrome type 3).
• CTPS1 defect: autosomal recessive mutation in the CTPS1 gene(CTPS1 stands for "CTP synthase 1"). The enzyme is necessary for the activation of T cells. The mutated enzyme leads to disturbances in T-cell activation. Furthermore: recurrent bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma. B- and T-cells and Ig possibly normal, memory B-cells decreased (see immunodeficiency 24).
• CD137 (41BB) defect: autosomal recessive mutation in the TNFRSF9 gene on chromosome 1p36.23 (TNFRSF9 stands for Tumor Necrosis Factor Receptor Superfamily Member 9). Clinically, the deficient gene product, a protein belonging to the ZNF receptor superfamily, leads to reduced IgG and IgA levels, T-cell proliferation, cytotoxicity and IFN-γ secretion. Furthermore, to EBV lymphoproliferation. Caution: Risk for the development of B cell lymphoma and chronic active EBV infection.
• RASGRP1 defect: autosomal recessive mutation in the RASGRP1 gene located on chromosome 15q14 (RASGRP1 stands for RAS Guanyl Releasing Protein 1). Clinically, the deficient protein leads to defects in B and T cell activation, proliferation, and motility. Naive T cells decreased. Furthermore: recurrent pneumonias, herpes infections. Cave: EBV-associated lymphoma (see belowimmunodeficiency 64).
• CARMIL2 (RLTPR) defect: autosomal recessive mutation in the CARMIL2 gene (CARMIL2 stands for Capping Protein Regulator And Myosin 1 Linker 2) located on chromosome 16q22.1. Clinically, the mutant CARMIL protein leads to an increase in CD4 (naïve CD4+ and CD8+ T cells are increased). Tregs and MAITs are decreased; CD28-induced function is decreased. This constellation leads to recurrent bacterial, mycobacterial and mycotic infections, viral warts, molluscs, EBV lymphoproliferation;furthermore to atopy phenomena and photodermatitis(immunodeficiency 58).
• MAGT1 defect: (MAGT1 stands for "Magnesium Transporter Protein 1"). X-linked recessive mutations in the MAGT1 gene located on chromosome Xq21.1 are associated with immunodeficiency, X-linked with magnesium defect, Epstein-Barr virus infection, and neoplasia/the mutation leads to a glycosylation defect. Clinical: increased propensity for EBV infection with an increased rate of lymphoma. Continued exposure to viral GI and respiratory infections. CD4 and RTE (recent thymic emigrants) decreased, CD4/CD8 inverted, MAITs decreased; poor proliferation on anti-CD3.
• PRKCD defect: (PRKCD stands for protein kinase C delta). AR/mutations in the PRKCD gene result in deficient protein kinase C, a member of the protein kinase C family that regulates cell survival, proliferation, and apoptosis. Clinically, these mutations lead to lymphoproliferation, recurrent bacterial and viral infections, hypogammaglobulinemia, chronic EBV infections, SLE-like autoimmunity (nephrosis, antiphospholipid syndrome) (see Autoimmune Lymphoproliferative Syndrome, Type III).