PID - combined T/B/NK immundeficiency- SCID and CID

The term "immunodeficiency diseases" (synonym: immunodeficiency syndromes) covers various diseases of the immune system that are characterized by a passive or irreversible disturbance of the immune function. Primary immunodeficiencies (PID) are diseases in which the 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).

In the case of combined T/B/(NK) cell immunodeficiencies incl. "SCID/ CID, both an antibody deficiency (reduction of immunoglobulins) and a restriction of cellular function may be present. The group is divided into:

• SCID (severe combined immunodeficiencies; in this case T- and B-cells are completely missing)
• and
• CID (less severe combined immunodeficiencies; these can also become symptomatic only in adulthood. In such cases, residual functions of the mutated proteins are present.

1.1.defects of humoral and cellular immunity (combined T/B/NK)-cell immunodeficiencies/ SCID (T-/B+).

• IL2RG deficiency: X-linked recessive mutations in the gamma -chain of IL-2,-4,-7,-9,-15,-21 receptors/severely reduced number of T and NK cells (see IL2RG gene below).
• JAK3 defect: AR/ mutations in JAK3 gene (encodes Janus kinase A)/ severely decreased number of T and NK cells.
• IL7R defect: AR/ mutations in IL7R gene/normal number of NK cells.
• CD45 defect: AR/mutations in the PTPRC gene (CD45 defect)/normal number of gamma/delta T cells.
• CD3D defect/immunodeficiency19: AR /mutations in CD3D gene/normal NK cells; no gamma/delta T cells.
• CD3E-defect/immunodeficiency18: AR/mutations in CD3E gene/normal NK cells; no gamma/delta T cells.
• CD247-defect/immunodeficiency25: AR/mutations in CD247 gene/1q24.2/normal NK cells; no gamma/detla T cells.
• CORO1A defect: mutation in CORA1A gene: AR/thymic tissue detectable; no expression of T cells; EBV-induced lymphoproliferation (see below EBV and recurrent infections).
• LAT defect/immunodeficiency52: AR/mutation in LAT gene/16q13/ adenopathy, splenomegaly, recurrent infections, autoimmunity; progressive combined ID, B and CD4 lymphopenia.

1.2.Defects of humoral and cellular immunity (combined T/B/NK)-cell immunodeficiencies /SCID (T-/B-).

• RAG1 defect (RAG stands for "recombination activating genes"): AR/mutations in RAG1 gene/11p12/disruption in VDJ recombination/Omenn syndrome.
• RAG2 defect: AR/mutations in the RAG2 gene/disruption in VDJ recombination/Omenn syndrome.
• DCLRE1C defect: AR/mutations in Artemis gene/10p13/defect in DNA recombinase repair protein, defective VDJ recombination. Increased sensitivity to ionizing radiation/Omenn syndrome.
• PRKDC -defect: AR/mutations in PRKDC gene/defect in DNA-PKcs of a subunit of a serine/threonine protein kinase/radiosensitivity increased/impaired VDJ recombination. Autoimmunity and granuloma formation possible/immune deficiency26 with or without neurological abnormalities.
• NHEJ1-(Cernunnos/XLF) defect: AR/mutation in NHEJ1 gene/increased radiosensitivity/impaired VDJ recombination/immune defect with microcephaly, developmental defects.
• LIG4- defect: AR/complex immunodeficiency syndrome caused by mutations in the LIG4 gene (Ligase4; 13q33 ) /increased radiosensitivity/impaired VDJ recombination/inconsistent microcephaly, developmental defects/LIG4 syndrome. LIG4 deficiency is also associated with multiple myeloma.
• ADA defect: AR/SCID with T and B cell defects due to mutations in ADA gene (20q13.12)/complex immunodeficiency/skeletal changes around costochondral junctions, liver and CNS symptoms and alveolar proteinosis possible/uric acid normal. Cave: Mild "delayed and late onset" variants are possible with milder symptoms.
• AK2 defect: AR/ mutations in AK2 gene /1p35.1./defective maturation of T and B cells and myeloid cells (=stem cell defect)/neutropenia, deafness possible/clinical: Immunodeficiency 73A with defective neutrophil chemotaxis and leukocytosis (OMIM: 608203)/recurrent bacterial and viral infections/lymphoproliferation, neutropenia.

1.3 Combined immunodeficiencies (CID - less severe than SCID)

• CD40 ligand deficiency:XCR/mutations in CD40LG gene/Xq26.3 (syn.TNFSF5/ CD154)/ impaired signaling in B- cells and dendritic cells, impaired switch process/ X-linked hyper IgM syndrome (su. Hyper IgM syndromes)/neutropenia,thrombocytopenia, hemolytic anemia, gastrointestinal:-liver involvement; opportunistic infections, including cryptosporidial infections (see cryptosporidiosis below) .
• CD40 -deficiency: AR/ mutations in CD40 gene/20q13.12 /impaired signaling in B and dendritic cells/neutropenia, gastrointestinal: liver involvement, opportunistic infections, also cryptosporidia (see below cryptosporodiosis).
• ICOS -defect: AR/mutations in ICOS gene/2q33.2 /ICOS enhances all basic T cell responses to a foreign antigen/mutations lead to pathological susceptibility to infection/autoimmunity.
• ICOS ligand defect: Autosomal recessive mutation in ICOSLG gene/21q22.3/ recurrent bacterial and viral infections, neutropenia.
• CD3G- defect: AR/ mutations in the gene for CD3G (CD3gamma)/reduced expression of the T-cell receptor/individual cases with autoimmunity/immune deficiency 17 (OMIM: 615607)/immune deficiency 19 (OMIM:615617).
• CD8A- defect: AR/ mutations in CD8A/CD8alpha gene/CD8 severely reduced or absent/ also asympotmatic courses.
• ZAP70- defect: AR/ LOF mutations in the ZAP70 gene. ZAP-70 is an important signal transduction element associated with the zeta chain in T cells/ CD8 cells decreased/ CD4 normal/ individual cases with autoimmunity or immune dysregulation.
• ZAP70 defect: AR/ combined hypomorphic and activating mutation (LOF/GOF) mutation in ZAP70 gene/ clinically autoimmunity (bullous pemphigoid, inflammatory colitis)/ CD8 reduced or absent with otherwise little altered B/T cell status.
• MHC class I defect: AR/mutations in TAP1 gene/no expression of MHC class I/ CD8 decreased, CD4 normal/ clinically: "Bare lymphocyte syndrome, type I" (OMIM: 604571), bronchial asthma, vasculitis, pyoderma gangraenosum.
• MHC class I defect: AR/mutations in TAP2 gene/6p21.32/clinical: Bare lymphocyte syndrome, type I (OMIM: 604571)/association with systemic scleroderma, lupus erythematosus, tuberculosis.
• MHC class I defect: AR/mutations in the TAPBP (tapasin) gene/6p21.32/clinical: Bare lymphocyte syndrome, type I (de la Salle H et al 1994; Furukawa H et al 1999) (OMIM: 604571).
• MHC- class I defect (= beta2-microglobulin defect): AR/mutations in the B2M gene. No expression of MHC I. Beta2-microglobulin is a component of the MHC class I complex, but also of CD1a-c and FcRn. Clinical: sinopulmonary infections, granulomas, hypoproteinemia.
• MHC class II defect, group A: AR/mutations in the transcription factor gene for MHC class II molecules - here CIITA /dyspepsia, diarrhea, respiratory and GI infections, biliary and liver disease/ CD4 often decreased.
• MHC class II defect, group B: AR/mutations in the transcription factor gene for MHC class II molecules here muttaions in RFXANK gene/19p13.11/about 70% of cases of MHC class II deficiencies!
• MHC class II defect, group C: AR/mutations in the transcription factor gene for MHC class II molecules/ here RFX5.
• MHC class II defect, group D: AR/mutations in the transcription factor gene for MHC class II molecules - here RFXAP
• IKAROS defect: AD/mutations in the IKZF1 gene /7p12.2 / recurrent sinopulmonary infections, PCP, (previously: CID with absent memory B- and T-cells)
• DOCK8 defect: AR/mutation in DOCK8 gene (DOCK8 stands for Dedicator Of Cytokinesis 8)/ 9p24.3/ T and NK lymphopenia, B cells increased; IgM low, IgE greatly increased, eosinophilia, similar to hyper IgE syndrome/ severe atopy, tendency to severe cutaneous bacterial, fungal and viral infections and malignancies.
• DOCK2 defect: AR/ mutation in DOCK2 gene (DOCK2 stands for Dedicator Of Cytokinesis 2)/5q35/required for RAC1 activation/actin polymerization, T cell proliferation, etc./NK number normal but function impaired.Low PHA response, low TREC, impaired IFN synthesis.
• Polymerase defects: AR/mutations in POLD 1/POLD2 genes/recurrent sinopulmonary and skin infections, molluscs, warts, short stature, intellectual deficits. IgG and CD4 low, B cells low with normal maturation.
• RhoH (RhoH steth for ras homolog gene family member H) defect: mutation in the RHOH gene, encoding an atypical Rho GTPase, a signal transduction element in diverse cells (AR; T cells and T cell function decreased, repertoire limited. HPV infections, lung granulomas, mollusca contagiosa, lymphomas).
• STK4 defect (MST1=macrophage stimulating 1 defect): AR/mutations in STK4 gene, a serine-threonine kinase/terminally differentiated effector memory cells (TEMRA) decreased/naïve T cells decreased with restricted T cell repertoire in TEMRA population, impaired T cell proliferation. IgM decreased, other Ig increased/recurrent bacterial, viral and Candida infections; intermittent neutropenia; EBV-triggered lymphoproliferation, lymphoma, congenital heart defects, autoimmune cytopenias; HPV infection.
• TCRalpha defect (immunodeficiency 7): AR/ mutations in the TRAC gene (T Cell Receptor Alpha Constant)/14q11.2/ absence of the TZR-alpha chain. All CD3 T cells carry TZRgamma/delta, T cell proliferation impaired/recurrent viral, bacterial and fungal infections, immune dysregulation, autoimmunity, diarrhea.
• LCK (lymphocyte-specific tyrosine kinase) defect: AR/mutation in the gene for a proximal tyrosine kinase/normal T-cell counts/CD4+ T-cell lymphopenia; low Treg; impaired T-cell repertoire, impaired TZR signaling/IgG and IgA normal, IgM possibly reduced/recurrent infections, immune dysregulation, autoimmunity, diarrhea.
• MALT1 defect (immunodeficiency 12): AR/mutations in MALT1 gene (MALT stands for "mucosa-associated lymphoid tissue protein-1"), a caspase-like cysteine protease/T-cell proliferation impaired/bacterial infections; fungal and viral infections/Ig normal with poor Ak formation.
• CARD11 (CARD stands for caspase recruitment domain): AR/LOF defect in CARD11 gene, part of "signalosome", necessary for NFκB activation/T and B cell numbers possibly normal, dysfunction/Bacterial and viral infections, PCP. Ig decreased or absent, T cells predominantly naive with poor function.
• BCL10 defect (immunodeficiency 37): AR/ mutations in BCL10 gene (B-cell lymphoma 10). Part of the "signalosome", necessary for NFkB activation/ clinical: recurrent bacterial, viral mycotic infections/ gastroenteritis/ B- and T-cell count possibly normal, function impaired.
• IL-21 defect: AR/mutation in IL21- gene/low B cells, hypogammaglobulinemia; severe early manifest colitis.
• IL-21R defect: AR/mutation in IL21R gene; receptor binds together with common γ-chain IL-21/ T and B cells possibly normal, very specific functional deficits. Susceptibility to PCP and cryptosporidia, cholangitis.
• TNFRSF4 (OX40/CD134) defect: defect in TNFRSF4, a major costimulatory molecule on activated T cells (AR; Kaposi's sarcoma. Impaired immunity to HHV8. B- and T-cell numbers normal, memory impaired). Clinically see below. Immunodeficiency 16 and TNFRSF4 defect.
• IKB (IκB kinase β) defect: AR/defect in the IKB gene encoding IkB kinase 2, an important component in the NF-κB activation pathway/clinical phenotype of SCID; bacterial, viral and fungal infections/no regulatory, no γ/δ T cells. B cells normal/activation of B and T cells but impaired.
• NIK (NF-κB-inducing kinase) defect: AR/mutations in MAP3K14 gene/ NIK deficiency =Primary immunodeficiency with multiple disorders of lymphoid immunity; ORPHA:447731/ bacterial and viral infections/ cryptosporidia. T cells normal with impaired function, B and switched memory B cells; NK cells decreased. Ig decreased.
• RelA haploinsufficiency: heterozygous mutation in RELA gene, haploinsufficiency (AD; mucocutaneous ulcerations. NFκB activation and synthesis of inflammatory cytokines impaired, responsive to anti-TNF administration).
• RelB defect: AR/mutation in RELB gene/recurrent infections/T-cell count normal but function and repertoire impaired. B-cells significantly elevated. Immunoglobulins normal but Ak formation impaired.
• MSN defect: XL/mutation in MSN gene/encoded protein = moesin/recurrent infections by bacteria and VZV. T cells normal, proliferation and migration impaired/progressive hypogammaglobulinemia.
• TFRC defect: AR/mutation in TFRC gene/recurrent infections, neutropenia, thrombocytopenia. T cells normal with impaired proliferation, memory B cells decreased.
• c-REL defect: AR/ AR/mutations in REL gene/infections by bacteria, mycobacteria, Salmonella and opportunists/decreased memory CD4 with impaired function, impaired B cell memory/Ak formation decreased.
• FCHO1 defect: AR/mutation in FCHO1/susceptibility to all types of microorganisms, lymphoproliferation, failure to thrive/T cells low, increased apoptosis, impaired clathrin-mediated endocytosis.

Typical opportunistic infections in severe combined immunodeficiencies in infants include Pneumocystis jiroveci or severe viral infections (CMV/EBV). In adults, typical infections are:aspergillosis, toxoplasmosis, adenovirus infections, Pneumocystis infections, cryptosporidiosis, systemic candidiasis, CMV retinitis or colitis, mycobacterioses. Furthermore, EBV-associated lymphomas, granulomatous inflammations can be found. These are an expression of insufficient pathogen elimination and consecutive autoinflammatory local reaction.