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 most important and best-known example of this is AIDS (acquired immune deficiency syndrome).

Patients with defects in intrinsic immunity also have recurrent invasive infections. This can include versch. Bacteria (e.g. Pneumococcus, Staphylococcus/ MyD88, IRAK4 defects) or warts(WHIM syndrome, Epidermodysplasia verruciformis) or fungal infections(Chronic Mucocutaneous Candidiasis). Defined defects in "innate immunity" affect cellular immune responses after cell activation via so-called Toll-like receptors (TLRs) or e.g. within signal processing via the NF-κB pathway.

Mendelian Susceptibility to Mycobacterial Diseases (MSMD)

• Interleukin-12/IL-23 receptor beta1 defect: AR/ mutations in the IL12RB1 and IL23RB1 genes (IL12/23RB1 stands for interleukin 12/23 receptor subunit beta1)/the IL12RB1 is located on chromosome 19p13.11, the IL23RB1 gene on chromosome 1p31.3/mutation leads to increased susceptibility to mycobacteria and salmonella. Impaired formation of IFN-gamma.
• Interleukin-12p40 defect: AR/mutation in the IL12B gene (IL12B stands for "Interleukin 12B"). The gene, which is located on chromosome 5q33.3, encodes the p40 subunit of IL-12 and IL-23. Mutations in this gene lead to increased susceptibility to mycobacteria and salmonella. The formation of IFN-γ is impaired.
• IL12RB2 (Interleukin-12RB2) defect: AR/mutation in the IL12RB2 gene (IL12RB2 stands for "Interleukin 12 Receptor Subunit Beta 2"/Chr. 1p31.3)/ encodes a type I transmembrane protein, a subunit of the interleukin-12 receptor complex/co-expression of this and the IL12RB1 protein leads to the formation of a high-affinity IL12 binding site that is necessary for IL12-dependent signal transmission/ mutations in this gene lead to increased susceptibility to mycobacteria and salmonella (see below Mendelian susceptibility to mycobacterial diseases)
• IFNGR1 defect : AD/mutation in the IFNGR1 gene/IFNGR1 stands for: Interferon Gamma Receptor 1/ mutation leads to increased susceptibility to mycobacteria and salmonella. No binding of IFN-γ, impaired signaling.
• IFNGR2 (IFN-gamma receptor 2) defect: AR/mutation in the IFNGR2 gene/chromosome 21q22.11/ IFNGR2 stands for: Interferon gamma receptor 2/ mutation leads to increased susceptibility to mycobacteria and salmonella (see MSDM, IFNGR2 defect below). Disturbed signaling/no signal through IFN-gamma.
• STAT1 defect (AD form): AD/mutation in the STAT1 gene (STAT1 stands for Signal Transducer And Activator Of Transcription 1), which is located on chromosome 2q32.2/the LOF mutation leads to increased susceptibility to mycobacteria/impaired IFN-γ signaling. Diseases associated with STAT1 include immunodeficiency 31B and immunodeficiency 31A.
• Macrophage gp91 PHOX defect: X-linked recessive germline mutation in the CYBB gene located on the cytogenetic band Xp21.1-p11.4 (CYBB stands for "Cytochrome B-245 Beta Chain"). The mutation leads to an isolated susceptibility to mycobacterial infections; furthermore, impaired "killing" by macrophages.
• IRF8 defect : autosomal dominant mutation in the IRF8 gene (IRF8 stands for interferon regulatory factor 8), which is located on chromosome 16q24.1. There is an isolated susceptibility to mycobacterial infections (see immunodeficiency 32A).
• IRF8 defect : autosomal recessive mutation in the IRF8 gene (IRF8 stands for interferon regulatory factor 8). The gene is located on chromosome 16q24.1. There is a susceptibility to viral infections (see immunodeficiency 32B).
• Tyk2 defect : autosomal recessive mutation in the TYK2 gene (TYK2 stands for tyrosine kinase 2), which is located on chromosome 19p13.2. Mutations in tyrosine kinase 2 lead to susceptibility to intracellular bacteria, fungi and viruses. Impaired signaling for various cytokines. Increased IgE possible (see belowMendelian Susceptibility to Mycobacterial Diseases - MSMD).
• P1104ATYK2 homozygosity: AR/mutation in the TYK2 gene (TYK2 stands for tyrosine kinase 2)/ chromosome 19p13.2 / mutation leads to an impaired response to IL-23 with an increased clinical susceptibility to mycobacterioses.
• ISG 15 defect: AR/mutation in the ISG15 gene (ISG15 stands for "ISG15 Ubiquitin Like Modifier"), which is located on chromosome 1p36.33. The gene codes for a type 1 interferon-inducible ubiquitin-like protein. The mutation leads to an increased susceptibility to mycobacteria. Calcifications in the brain and impaired formation of IFN-gamma are also found.
• RORC defect: AR/mutation in the RORC gene (RORc stands for "RAR-related orphan receptor C"), which is localized on chromosome 1q21/mutation in the RORC gene leads to increased susceptibility to mycobacteria and Candida (see also Mendelian susceptibility to mycobacterial diseases; see Immunodeficiency 42). This is caused by a lack of IFN-γ production and a complete absence of IL-17A/F-producing T cells.
• JAK1 LOFdefect: AR/mutation in the JAK1 gene (JAK1 stands for Janus kinase 1), which is located on chromosome 1p31.3. The mutation results in reduced JAK1 activation and reduced IFN-γ production. Increased susceptibility to mycobacteria and viruses. Tendency to urothelial carcinoma.
• Epidermodysplasia verruciformis group
• EVER1 (TMC6) defect: AR/mutations in the TMC6 gene (TMC6 stands for "Transmembrane Channel Like 6"), which is located on chromosome 17q25.3. The gene codes for a channel-like transmembrane protein with 10 transmembrane domains and 2 leucine zipper motifs. Both EVER (Epidermodysplasia Verruciformis) proteins together with CIB1 form a complex in keratinocytes. Mutations in the TMC6 gene lead to the clinical picture of epidermodysplasia ver ruciformis, which is characterized by HPV (group B1) infections and skin cancer.
• EVER2 (TMC8) defect: autosomal recessive mutations in the TMC8 gene (TMC6 stands for "Transmembrane Channel Like 8"), which is located on chromosome 17q25.3. The gene codes for a channel-like transmembrane protein with 10 transmembrane domains and 2 leucine zipper motifs. Both EVER (Epidermodysplasia Verruciformis) proteins together with CIB1 form a complex in keratinocytes. Mutations in the TMC6 gene lead to the clinical picture of epidermodysplasia ver ruciformis, which is characterized by HPV (group B1) infections and skin cancer.
• CIB1 defect: AR/mutations in the CIB1 gene (CIB1 stands for "Calcium And Integrin Binding 1")/Chr.15q26.1/ gene encodes a member of the EF-hand domain-containing calcium-binding superfamily/ protein interacts with many other proteins/ may be involved in cell survival and proliferation/ mutations are associated with several diseases, including HPV (group B1) infections (see also epidermodysplasia verruciformis).
• CXCR4 defect(WHIM syndrome/WHIM stands for: warts, hypogammaglobulinemia, infections, myelocathexis)/ AD/ "gain-of-function mutation" in the CXCR4 gene(CXCR4 stands for "C-X-C Motif Chemokine Receptor 4"; chromosome 2q22.1). The gene codes for the receptor of the chemokine CXCL12.
• Predisposition to other severe viral infections.
• STAT1 LOF defect: autosomal recessive LOF mutations in STAT1. (STAT1 stands for Signal Transducer And Activator Of Transcription 1), which is located on chromosome 2q32.2. The mutation leads to disorders of the STAT1-dependent response to IFN-α, IFN-ß, IFN-γ and IFN-λ. Furthermore, there are disorders in T and NK cells that are clinically characterized by severe viral and mycobacterial infections.
• STAT2 defect: autosomal recessive mutations in the STAT2 gene(STAT2 stands for Signal Transducer And Activator Of Transcription 2), which is located on chromosome 12q13.3. The immunological response to type 1/3 interferons is impaired Disruption of the STAT2-dependent response to IFN-alpha, IFN-gamma. Disturbances in T and NK cells. Clinically, the syndrome is characterized by severe viral infections, e.g. disseminated vaccine measles.
• IRF9 defect: autosomal recessive mutation in the IRF9 gene (IRF9 stands for "Interferon Regulatory Factor 9"), which is located on chromosome 14q12. Mutations in the IRF9 gene lead to severe influenza (see also immunodeficiency 65/mutation in the IRF9 gene).
• IRF7 defect: AR/ mutation in the IRF7 gene (IRF7 stands for Interferon Regulatory Factor 7) located on chromosome 11p15.5/IRF7 encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family/encoded protein plays an important role in the innate immune response against DNA and RNA viruses/mutations in the IRF7 gene lead to impaired response to IFN-α, IFN-ß, IFN-γ and IFN-gamma. Severe influenza infections are clinically conspicuous.
• IFNAR1 defect: AR/mutations in the IFNAR1 gene (IFNAR1 stands for "Interferon Alpha And Beta Receptor Subunit 1") located on chromosome 21q22.11/ the encoded protein is a type I membrane protein and belongs to the type II cytokine receptor family/ it forms one of the two chains of the receptor for interferon alpha and beta/ the binding and activation of the receptor stimulates Janus protein kinases, which phosphorylate several proteins, including STAT1 and STAT2/ mutations in this gene lead to disorders of the response to type I interferons, as well as to severe vaccination complications after yellow fever or measles vaccination.
• IFNAR2 defect: AR/mutations in the IFNAR2 gene (IFNAR2 stands for "Interferon alpha and beta receptor subunit 2"/ Chr. 21q22.11)/ encoded protein is a type I membrane protein/ family of type II cytokine receptors/ forms one of the two chains of the receptor for the interferons alpha and beta/ binding and activation of the receptor stimulates Janus protein kinases/phosphorylates STAT1 and STAT2/ mutations lead to disorders of the response to type I interferons, e.g. to disseminated vaccine measles or HHV-6 infections.
• CD16 defect (low-affinity Fcg receptor): AR/mutations in the FCGR3A gene (FCGR3A stands for "Fc Fragment Of IgG Receptor IIIa") which is localized on chromosome 1q23.3/mutations lead to susceptibility to severe viral infections, e.g. HSV, EBV, HPV.
• MDA5 LOF defect: AR/ LOF mutations in the IFIH1 gene (IFIH1 stands for "Interferon Induced With Helicase C Domain 1") located on chromosome 2q24.2/mutations in this gene lead to susceptibility to rhinoviruses and other RNA viruses.
• RNA polymerase III defect: AD/mutations in the POLR3A, POLR3c or POLR3F genes/mutations lead to impaired virus recognition and impaired IFN production after viral contact. Severe varicella infections are clinically conspicuous.
• Herpes simplex encephalitis
• TLR3 defect: AR or AD/ mutations in the TLR3 gene, involved in the formation of IFN-α, -β, -λ. Defect in CNS cells and fibroblasts. Clinically, there is an increased risk of contracting HSV-1 encephalitis (incomplete penetrance for this and subsequent defects). Severe influenza or varicella also possible
• UNC93B1 (unc-93 homolog B1): autosomal recessive defect in the UNC93B1 gene. The encoded protein is involved in the formation of IFN-α, -β, -λ. The mutation leads to an increased risk of contracting HSV-1 encephalitis. Defect in cells of the CNS and fibroblasts.
• TRAF3 (TNF receptor associated factor 3) defect: TRAF3 is involved in the formation of IFN-α, -β, -λ. The mutation leads to an increased risk of contracting HSV-1 encephalitis. Defect in cells of the CNS and fibroblasts.
• TRIF defect: autosomal dominant or autosomal recessive mutation in TICAM1 (TICAM1 stands for toll-like receptor adaptor molecule 1). The encoded protein is involved in the formation of IFN-α, -β, -λ. The mutation leads to an increased risk of contracting HSV-1 encephalitis. Defect in cells of the CNS and fibroblasts.
• TBK1 defect: autosomal dominant mutation in the TBK1 gene (TBK1 stands for "TANK-binding kinase 1"). The protein encoded by this gene is involved in the formation of IFN-α, -β, -λ. The mutation leads to an increased risk of contracting HSV-1 encephalitis. Defect in cells of the CNS and fibroblasts.
• IRF3 defect: autosomal dominant mutation in the IRF3 gene. HSV-1 encephalitis. The protein encoded by this gene is involved in the production of IFN-α, -β, -λ. The mutation leads to an increased risk of contracting HSV-1 encephalitis. Defect in cells of the CNS and fibroblasts.
• DBR1 defect: autosomal recessive mutation in the DBR1 gene. The protein encoded by this gene is involved in the production of antiviral interferons. The mutation leads to an increased risk of contracting brain stem infections caused by HSV and other viruses.
• Disposition to invasive fungal infections
• CARD9 defect: AR/mutation in the CARD9 gene, which is located on chromosome 9q34.3. The protein encoded by the CARD9 gene (CARD9 stands for "Caspase Recruitment Domain Family Member 9") is a member of the CARD protein family, which is defined by the presence of a characteristic caspase-associated recruitment domain (CARD). CARD9 plays an important regulatory role in cell apoptosis. The CARD9 mutation leads to a disturbed signaling pathway. This results in invasive Candida infections, deep dermatophytoses and invasive infections with other fungi.
• Chronic mucocutaneous candidiasis (CMC)
• IL-17RA defect: AR/mutations in the IL17RA gene (IL17RA stands for "Interleukin 17 Receptor A") which is localized on chromosome 22q11.1/no IL17 signal can be induced by the mutated receptor protein. The clinical consequence is"chronic mucocutaneous candidiasis". The defect (loss of receptor) affects epithelial cells, fibroblasts and monocytes (seeImmunodeficiency 51).
• IL-17RC defect: autosomal recessive mutation in the IL17RC gene (IL17RC stands for "Interleukin 17 Receptor C") which is located on chromosome 3p25.3. The mutated receptor protein means that no signal can be induced by IL-17. The clinical consequence is chronic mucocutaneous candidiasis and folliculitis. The defect affects epithelial cells, fibroblasts and monocytes.
• IL-17F defect: autosomal dominant mutation in the IL17F gene (IL17F stands for Interleukin-17F which is localized on chromosome 6p12.2. The mutation in the IL17F gene leads to a deficient IL17F. The clinical consequence is chronic mucocutaneous candidiasis, folliculitis.
• STAT1 (GOF) mutation: AD/mutation in the STAT1 gene (STAT1 stands for "Signal Transducer And Activator Of Transcription 1"; 2q32.2)/ the STAT1 protein is a member of the STAT protein family and can be activated by various ligands such as interferon-alpha, interferon-gamma, EGF, PDGF and IL6. The protein plays an important role in immune reactions to viral and mycobacterial pathogens. Mutations in this gene are associated with the immunodeficiencies 31B, 31A and 31C (chronic mucocutaneous candidiasis). Furthermore, autoimmunological diseases occur more frequently (thyroiditis, diabetes, cytopenias).
• ACT1 defect: autosomal recessive mutation in the TRAF3IPT2 gene (TRAF3IPT2 stands for "TRAF3 Interacting Protein 2") located on chromosome 6q21. The gene codes for Act1, a major adaptor in the IL-17A signaling pathway. The mutation leads to a lack of response to IL-17 isoforms: fibroblasts do not respond to IL-17A and F, T cells do not respond to IL-17E. The clinical consequences are"chronic mucocutaneous candidiasis", folliculitis, blepharitis, macroglossia.
• Disturbance of TIR (Toll-like and Interleukin-1R) signaling with susceptibility to bacteria
• IL-1 receptor associated kinase 4 (IRAK4) deficiency: autosomal recessive mutation in the IRAK4 gene, which is located on chromosome 12q12. The gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. This kinase is essential for most innate immune responses. Mutations in this gene lead to IRAK4 deficiency, to disorders of TLR and IL-1R signaling, to defects in lymphocytes, granulocytes and monocytes. Recurrent invasive pneumococcal disease is the main clinical manifestation, and several transcript variants encoding different isoforms have been found for this gene.
• MyD88 defect: AR/mutation in the MyD88 gene (MyD88 stands for "Myeloid Differentiation Primary Response Protein MyD88"), which is located on chromosome 3p22.2/the encoded protein "MYD88" is an adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response/acts via IRAK1, IRAK2, IRF7 and TRAF6 and leads to NF-kappa-B activation, Cytokine secretion and inflammatory response/ Mutations lead to bacterial infections, disruption of TLR and IL-1R signaling/ Diseases associated with MYD88 include immunodeficiency 68 and macroglobulinemia, Waldenström 1 (s.a. Macroglobulinemia, Waldenström).
• IRAK1 defect: Xchromosomal recessive mutation in the IRAK1 gene (IRAK1 stands for "Interleukin 1 Receptor Associated Kinase 1") located on chromosome Xq28. The receptor-associated kinase encoded by this gene is a serine/threonine kinase that associates with the interleukin-1 receptor (IL1R) when stimulated. Mutations in this gene lead to defects in lymphocytes, granulocytes and monocytes. The main clinical manifestations are bacterial infections. Diseases associated with IRAK1 include "systemic lupus erythematosus" and the X-linked MECP2 defect syndrome due to a large de novo Xq28 chromosomal deletion including MECP2 and IRAK1.
• TIRAP defect: autosomal recessive mutation in the TIRAP gene (TIRAP stands for "Toll/Interleukin-1 Receptor Domain-Containing Adapter Protein"), which is located on chromosome 11q24.2. The encoded protein, a TIR adaptor protein involved in the TLR4 signaling pathway of the immune system, activates NF-kappa-B, MAPK1, MAPK3 and JNK, which leads to cytokine secretion and an inflammatory response. Dysfunction of this adapter protein leads to disruption of signaling via TLR1/2, TLR2/6 and TLR4 in fibroblasts and leukocytes. Staphylococcal infections become clinically evident at an early stage.
• Other congenital defects of immunity involving non-hematopoietic tissues
• Isolated congenital asplenia (ICA) with RPSA defect: autosomal dominant mutation in the RPSA gene (RPSA stands for "Ribosomal Protein SA") located on chromosome 3p22.1. This gene encodes a high-affinity laminin receptor 1, which does not belong to the integrin family. This receptor is also known as 67 kD laminin receptor, 37 kD laminin receptor precursor (37LRP) and p40 ribosome-associated protein. The amino acid sequence of laminin receptor 1 is highly conserved throughout evolution, suggesting a key biological function. ICA syndrome (CD-10: Q89.0; OMIM: 271400) is characterized by the absence of the spleen and by severe, recurrent, serious infections (especially pneumococcal sepsis) in otherwise apparently healthy infants.
• HMOX defect with isolated congenital asplenia (ICA): autosomal recessive mutation in the HMOX gene (HMOX stands for "heme oxygenase") which codes for heme oxygenase, an essential enzyme in heme catabolism. The enzyme cleaves heme to biliverdin, which is subsequently converted to bilirubin by biliverdin reductase, and to carbon monoxide, a putative neurotransmitter. Heme oxygenase occurs in the form of 2 isoenzymes, an inducible heme oxygenase-1 and a constitutive heme oxygenase-2 (HMOX1 and HMOX2). Clinically, the signs of ICA are present, as well as hemolysis, nephritis and inflammation.
• APOL1 nucleotide variants/trypanosomiasis resistance: Nucleotide variants in the APOL1 gene (APOL1 stands for apolipoprotein L1), which is located on chromosome 22q12.3, contribute to the increased risk of kidney disease in people of African descent. The high allele frequency of these variants is thought to be due to the resistance they confer to the disease-causing trypanosome species involved in African sleeping sickness in humans. People of African descent have an increased risk of developing chronic kidney disease, mainly due to two variants in the apolipoprotein L1 (APOL1) gene that are unique to people of West African descent. These variants are thought to be genetically dominant because they provide protection against African sleeping sickness, which is caused by the parasite Trypanosoma brucei.
• NBAS defect and acute liver failure: autosomal recessive mutation in the NBAS gene (NBAS stands for "Neuroblastoma-Amplified Gene Protein"), which is located on chromosome 2p24.3. The encoded protein is apparently involved in Golgi-to-ER transport. Mutations in this gene are associated with short stature, optic nerve atrophy and Pelger-Huët anomaly. This is an autosomal-dominantly inherited laminopathy in which the leukocyte nucleus is malformed. In homozygous carriers, functional disorders of the granulocytes and other symptoms may occur. Furthermore, fever-induced liver failure.
• RANBP2 defect and acute necrotizing encephalopathy: autosomal dominant mutation in the RANBP2 gene (RANBP2 stands for "RAN Binding Protein 2"), which is located on chromosome 2q13. The gene encodes a very large RAN-binding protein that is immunolocalized to the nuclear pore complex. Diseases associated with RANBP2 include "acute necrotizing encephalitis".
• CLCN7 defect and osteopetrosis: autosomal recessive mutation in the CLCN7 gene (CLCN7 stands for "Chloride Voltage-Gated Channel 7") located on chromosome 16p13.3. CLCN7 codes for a chloride channel protein (chloride channel 7). Chloride channels play an important role in the plasma membrane and in intracellular organelles. Defects in this gene are the cause of autosomal recessive osteopetrosis type 4 (OPTB4) and autosomal dominant osteopetrosis type 2 (OPTA2; marble disease). Osteopetrosis is a rare genetic disease characterized by abnormally compacted bones.
• SNX10 defect and osteopetrosis: autosomal recessive mutation in the SNX10 gene.
• OSTM1 defect and osteopetrosis: autosomal recessive mutation in the OSTM1 gene.
• PLEKHM1 defect and osteopetrosis: autosomal recessive mutation in the PLEKHM1 gene.
• TCIRG1 defect and osteopetrosis: autosomal recessive mutation in the TCIRG1 gene.
• TNFRSF11A defect and osteopetrosis: autosomal recessive mutation in the TNFRSF11A gene.
• TNFSF11 defect and osteopetrosis: autosomal recessive mutation in the TNFSF11 gene.
• NCSTN defect and hidradenitis suppurativa: AD/mutation in the NCSTN gene (NCSTN stands for "Nicastrin") which is located on chromosome 1q23.2. The NCSTN gene encodes a type I transmembrane glycoprotein that is an integral part of the multimeric gamma-secretase complex. The encoded enzyme cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein. The cleavage of beta-amyloid precursor protein leads to amyloid beta peptide, the main component of neuritic plaques in the brains of Alzheimer's patients. Mutations in the NCSTN gene are associated with"familial acne inversa".
• PSENEN 2 defect and hidradenitis suppurativa: AD/mutation in the PSENEN2 gene (see there). PSENEN codes for the protein PSEN2. The encoded protein is an important subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid beta precursor protein).
• PSEN2 defect: modulates both the endoproteolysis of presenilin and gamma-secretase activity. Mutations leading to haploinsufficiency of the gene are associated with familial hidradenitis suppurativa (see below Acne inversa-2 - ACNINV2 with or without Dowling-Degos disease (OMIM: 613736). Alternative splicing leads to several transcript variants.
• Other congenital defects in leukocytes
• IRF4 defect: AD/mutation in the IRF4 gene (IRF4 stands for "Interferon Regulatory Factor 4") located on chromosome 6p25.3. The IRF4 gene encodes a member protein of the IRF (interferon regulatory factor) family of transcription factors characterized by a unique tryptophan pentad repeat DNA binding domain. The IRFs play an important role in the regulation of interferons in response to viral infection and in the regulation of interferon-inducible genes. A chromosomal translocation involving this gene and the IgH locus, t(6;14)(p25;q32), may be a cause of multiple myeloma. Other diseases associated with IRF4 include skin/hair/eye pigmentation and Whipple disease.
• IL18BP defect: Mutation in the IL18BP gene (IL18BP stands for "Interleukin 18 Binding Protein") located on chromosome 11q13.4. The protein encoded by this gene acts as an inhibitor of the pro-inflammatory cytokine IL18, binding IL18, preventing IL18 from binding to its receptor and thus inhibiting IL18-induced IFN-gamma production, resulting in a reduced T helper type 1 immune response. Diseases associated with IL18BP dysfunction include fulminant viral hepatitis A and molluscum contagiosum.