PID autoinflammatory diseases

Last updated on: 23.06.2022

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Definition
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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).

Recently, due to widespread molecular genetic diagnostics, new monogenetic autoinflammatory diseases are increasingly being elucidated. Their phenotypes show overlaps with the classical primary immunodeficiencies listed so far. Leading symptoms of severe autoinflammatory diseases include periodic or persistent fever of unclear cause, polyserositis, exanthema, and also severe or early-onset (<1 year of age) colitis or the various forms of FACS (Familial Immunodeficiency Syndrome). Forms of FACS (Familial forms of cold urticaria) or chronic hidradenitis suppurativa. Therapeutically, a broad immunosuppressive therapy or cytokine-specific inhibition of autoinflammation may be indicated.

When clinically assigning a clinical picture, the following procedure is recommended (N.Wagner et al. 2022):

  • Initial clinical evidence of autoinflammatory disease.
  • Recognition of a disease-specific pattern (e.g., recurrent fever episodes).
  • When did the first symptoms of disease occur?
  • How long do the fever episodes last?
  • What is the time interval between episodes (duration, variability, periodicity)?
  • Can trigger factors of the attacks be determined?
  • How does the disease develop over time?
  • What is the therapeutic response?
  • Family history, consanguinity and ethnicity?
  • Can signs of immune deficiency be elicited?
  • Organ involvement as an indication of autoinflammatory diseases
  • Laboratory diagnostics in autoinflammatory diseases
  • Classification/diagnosis criteria
  • Genetic diagnostics
  • Management of autoinflammatory diseases

Classification
This section has been translated automatically.

Type 1 Interferonopathies

  • STING1 defect: AR/mutation in the STING1 gene (TMEM173 gene) (STING 1 stands for Stimulator Of Interferon Response CGAMP Interactor 1) which is located on chromosome 5q31.2. The STING1 gene encodes a transmembrane protein that functions as an important regulator of the innate immune response to viral and bacterial infections. The STING1 protein is a pattern recognition receptor that recognizes cytosolic nucleic acids and relays signals that activate type I interferon responses. Mutations in this gene are the cause of childhood-onset STING-associated vasculopathy (SAVI ), inflammatory lung disease, systemic autoinflammation(familial chilblain lupus).
  • ADA2 defect: AR/ mutation in the ADA2 gene (ADA stands for "Adenosine Deaminase 2") which is localized on chromosome 22q11.1. The ADA2 gene encodes a member of a subfamily of the adenosine deaminase protein family. ADA2 is one of two adenosine deaminases found in humans, enzymes that regulate levels of the signaling molecule adenosine. The encoded protein is secreted by monocytes, and may regulate cell proliferation and differentiation. Diseases associated with ADA2 include Sneddon syndrome and vasculitis, autoinflammation, immunodeficiency and hematologic defect syndrome.
  • TREX1 defect: autosomal recessive mutation in the TREX1 gene (TREX1 stands for "three prime repair exonuclease 1, = DNase III") which is located on chromosome 3p21.31. The TREX1 gene encodes a nuclear protein with 3' exonuclease activity. This nuclease may play a role in DNA repair and serves as a proofreading function for DNA polymerase. Mutations in this gene lead to Aicardi-Goutieres syndrome as well as familial Chilblain lupus, Cree encephalitis, and other immune system disorders.
  • RNASEH2B defect: Mutations in the RNASEH2B gene (RNASEH2B stands for "Ribonuclease H2 Subunit B") located on chromosome 13q14.3. The RNASEH2B gene encodes a nuclease subunit and specifically degrades RNA from RNA:DNA hybrids. The protein encoded by this gene is the non-catalytic subunit B of RNase H2, which is thought to play a role in DNA replication. Defects in this gene are one of the causes of polygenic Aicardi-Goutières syndrome type 2 (AGS2).
  • RNASEH2C defect: autosomal recessive mutation in the RNASEH2C gene (ribonuclease H2 subunit C) located on chromosome 11q13.1. The RNASEH2C gene encodes a nuclease subunit that can cleave ribonucleotides from RNA-DNA duplexes. Mutations in this gene cause Aicardi-Goutieres syndrome-3, a disease with severe neurological dysfunction.
  • RNASEH2A defect: autosomal recessive mutation in the RNASEH2A gene (ribonuclease H2 subunit A) which is located on chromosome 19p13.13. The RNASEH2A gene encodes a protein that forms a component of the heterotrimeric type II ribonuclease H enzyme (RNAseH2). RNAseH2 is the major source of ribonuclease H activity in mammalian cells and endonucleolytically cleaves ribonucleotides. Mutations in this gene cause Aicardi-Goutières syndrome (AGS), an autosomal recessively inherited neurological disorder characterized by progressive microcephaly and psychomotor retardation, intracranial calcifications, elevated levels of interferon-alpha, and white blood cells in cerebrospinal fluid.
  • SAMHD1 defect: autosomal recessive mutations in the SAMHD1 gene (SAMHD1 stands for "SAM And HD Domain Containing Deoxynucleoside") which is located on chromosome 20q11.23. The SAMHD1 gene encodes a protein that is upregulated in response to viral infection. It may be involved in mediating proinflammatory tumor necrosis factor-alpha responses. Mutations in this gene have been associated with Aicardi-Goutières syndrome , as well as Chilblain lupus 2(familial Chilblain lupus).
  • ADAR defect: AR/mutation in the ADAR gene (ADAR stands for "Adenosine Deaminase, RNA-specific)/ chromosome 1q21.3 /. The ADAR1 gene encodes a deaminase responsible for RNA editing by site-specific deamination of adenosines/destabilizes double-stranded RNA by converting adenosine to inosine/mutations in this gene have been associated with dyschromatosis symmetrica hereditaria and Aicardi-Goutières syndrome 6.
  • IFIH1 defect: AR/mutation in the IFIH1 gene (IFIH1 stands for "Interferon Induced With Helicase C Domain 1") /chromosome 2q24.2/ Gene encodes MDA5, an intracellular sensor for viral RNA that triggers the innate immune response/MDA5 recognizes the length and secondary structure of RNA and binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and C-terminal domain, resulting in a proinflammatory response, which includes interferons/Coronaviruses (CoVs) can bypass the MDA5-dependent interferon response/MDA5 also plays an important role in NK cell function in malaria infections/MDA5 dysfunctions play a role in autoimmunological and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, MDA5-positive dermatomyositis; Aicardi-Goutières syndrome 7 and Singleton-Merten syndrome.
  • DNAse II defect: autosomal recessive mutation in the DNASE2 gene (DNASe2 stands for Deoxyribonuclease 2, Lysosomal II) which is located on chromosome 19p13.13. The enzyme degrades DNA. Loss of DNase II activity induces type I interferon signaling. Mutations in the DNASE2 gene are associated with classic Aicardi-Goutieres syndrome (AGS) and systemic lupus erythematosus.
  • DNASE1L3 defect: AR/mutation in the DNASE1L3 gene (DNASE1L3 stands for deoxyribonuclease 1 like 3/ 3p14.3). The gene product is an endonuclease that degrades extracellular DNA/absence of the product impairs elimination of apoptotic cells/ clinically manifests very early infantile SLE/ furthermore the mutation is associated with hypocomplementemic urticarial vasculitis (HUVS).
  • ACP5 defect: AR/mutation in the ACP5 gene (ACP5 stands for "Acid Phosphatase 5 Tartrate Resistant ") which is located on chromosome 19p13.2. The protein encoded by the ACP5 gene is a tartrate-resistant acid phosphatase (TRAP). The enzyme causes upregulation of IFN-α. Mutations in the ACP5 gene are associated with recurrent bacterial and viral infections, intracranial calcifications, SLE-like autoimmunity, Raynaud's symptoms, vitiligo, thrombocytopenia, autoimmune hemolytic anemia, short stature, skeletal dysplasia (spondyloenchondrodysplasia with immune dysregulation - SPENCD); furthermore hair cell leukemia.
  • POLA1 defect: X-linked mutation in POLA1 gene (POLA1 stands for DNA Polymerase Alpha 1, Catalytic Subunit) located in chromosomal section Xp22.11-p21.3. The POLA1 gene product is required for the synthesis of cytosolic RNA-DNA. In its absence, there is increased IFN-I production with hyperpigmentation, amyloidosis, characteristic facies, lung and GI involvement. Diseases associated with POLA1 include Van Esch-O'driscoll syndrome and X-linked reticular pigment disorder with systemic manifestations.
  • USPO18 defect: Mutations in the USPO18 gene (USPO18 stands for "Ubiquitin Specific Peptidase 18") which is located on chromosome 22q11.2. The protein encoded by this gene belongs to the family of ubiquitin-specific proteases (UBP), which cleave ubiquitin from ubiquitinated protein substrates. It is highly expressed in liver and thymus and is localized in the nucleus. Diseases associated with USP18 include pseudo-Torch syndrome (OMIM: 251290).
  • OAS1 defect: autosomal recessive mutations in the OAS1 gene (OAS1 stands for "2'-5'-oligoadenylate synthetase 1") which is located on chromosome 12q24.13. The gene is induced by interferons and encodes an enzyme that activates latent RNase L, leading to degradation of viral RNA and inhibition of viral replication. Polymorphisms in this gene have been associated with susceptibility to viral infections and type 1 diabetes mellitus. Diseases associated with OAS1 include infantile-onset pulmonary alveolar proteinosis with hypogammaglobulinemia .

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  • Disease patterns caused by defects of the inflammasome:
  • MEFV defect: autosomal recessive LOF mutations or autosomal dominant mutations in the MEFV gene (MEFV stands for "MEFV Innate Immuity Regulator, Pyrin") which is located on chromosome 16p13.3. The protein encoded by the MEFV gene, also known as pyrin or marenostrin, is an important modulator of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Mutations in this gene are associated with Mediterranean fever, a hereditary periodic fever syndrome, and neutrophilic dermatosis. MEFV mutations are more common in hidradenitis suppurativa than in the normal population. They are associated with disease severity but are also of prognostic significance in many other inflammatory diseases.
  • MVK defect: autosomal recessive mutation in the MVK gene (MVK stands for "Mevalonate Kinase") located on chromosome 12q24.11. The protein encoded by this gene is the peroxisomal enzyme mevalonate kinase an important early enzyme in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene leads to mevalonic aciduria, a disease characterized by psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia, and recurrent febrile crises. Defects in this gene also cause hyper-IgD syndrome and periodic fever syndrome (urticarial exanthema).
  • NLRP3 defects: Mutations in the NLRP3 gene (NALP3 stands for "NACHT, LRR and PYD domains-containing protein") located on chromosome 1q44 are associated with the following disorders: Muckle-Wells syndrome (urticarial exanthema), cold-induced autoinflammatory syndrome 1, familial (reference: Probably identical to Muckle-Wells syndrome), NOMID (neonatal onset multisystem inflammatory disease) (urticarial exanthema), CINCA (chronic infantile neurologic cutaneous and articular syndrome)(urticarial exanthema).
  • NLRC4 defects: Mutations in the NLRC4 gene (NLRC4 stands for "Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And CARD Domain Containing 4") is located on chromosome 2p22.3. Mutations in this gene are associated with cold-induced autoinflammatory syndrome 4, familial . NLRC4 encodes a member of the caspase recruitment domain-containing NLR family. Members of this family play an essential role in the innate immune response to a broad spectrum of pathogenic organisms, tissue damage, and other cellular stresses.
  • NLRP12 Defects: The NLRP12 gene (NLRP12 stands for "NLR Family Pyrin Domain Containing 12") is a protein-coding gene located at chromosome 19q13.42. The NLRP12 gene encodes a member of the so-called CATERPILLER family of cytoplasmic proteins. The encoded protein, which contains an N-terminal pyrin domain, a NACHT domain, a NACHT-associated domain, and a C-terminal leucine-rich repeat region, acts as an anti-inflammatory factor by suppressing inflammatory responses in activated monocytes. Mutations in this gene that cause deficiency of the encoded protein cause Familial Cold-Induced Autoinflammatory Syndrome 2 .

  • PLCG2 defect: The PLAID gene (PLAID stands for "phospholipase C gamma 2") is located on chromosome 16q24.1and encodes a transmembrane signaling enzyme that catalyzes the conversion of 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate to 1D-myo-inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) using calcium as a cofactor. IP3 and DAG are second messenger molecules important for the transmission of signals from growth factor receptors and immune system receptors across the cell membrane. Mutations in this gene lead to activation of IL-1 signaling pathways. They are associated with autoinflammation, antibody deficiency, and immune dysregulation, as well as with cold-induced autoinflammation syndrome 3, familial /614468/ (see also Familial Cold Urticaria).
  • NLRP1 defect: autosomal recessive mutations in the NLRP1 gene (NLRP1 stands for "Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 1") located on chromosome 17p13 result in systemic elevation of IL-18 and caspase-1. NLRP1 gene mutations are associated with: Palmoplantar Carcinoma, Multiple Self-Healing (OMIM:615225, palmo-plantar keratoacanthomas).
  • NLRP1 GOF defect: autosomal GOF mutations in NLRP1 (NLRP1 stands for "Nucleotide-Binding Oligomerization Domain, Leucine Rich Repeat And Pyrin Domain Containing 1") located on chromosome 17p13 lead to the clinical picture of "Respiratory Papillomatosis, Juvenile Recurrent, Congenital (OMIM: 618803) with recurrent respiratory papillomatosis, palmar and plantar warts, keratosis pilaris, atrophodermia vermiculata.

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  • Non-Inflammasone Dependent Autoinflammation.
  • TNFRSF1A defect: autosomal recessive mutations in the TNFRSF1A gene (TNFRSF1A stands for "Tumor Necrosis Factor Receptor Superfamily, Member 1A") which is located on chromosome 12p13.31localize to impaired signaling via TNF. The associated clinical picture "TRAPS" (TNF Receptor-associated Periodic Syndrome) is characterized by recurrent fever, serositis, urticarial exanthema, arthritis.
  • PSTPIP1 defect: autosomal dominant mutations in PSTPIP1 gene (PSTPIP1 stands for "Proline-Serine-Threonine Phosphatase-Interacting Protein 1) which is located on chromosome 15q24.3, lead to impaired actin reorganization and PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, acne) with hyperzincemia and hypercalprotectinemia as well as destructive arthritis, inflammatory urticarial exanthema and myositis. Associations also exist with pyoderma gangraenosum.
  • NOD2 (syn.CARD15): autosomal dominant mutations in the NOD2 gene(NOD2 stands for Nucleotide Binding Oligomerization Domain Containing 2) located on chromosome 16q12.1. Mutations in this gene are associated with Blau syndrome : granulomatous arthritis, lichenoid granulomatous dermatitis, refractory uveitis. 30% of carriers develop Crohn's disease.
  • ADAM17 defect: autosomal recessive mutation in the ADAM17 gene (ADAM17 stands for "ADAM metallopeptidase domain 17", located on chromosome 2p25.1. ADAM17 (ADAM metallopeptidase domain 17) is a protein coding gene. Diseases associated with ADAM17 include: Inflammatory Skin and Bowel Disease, Neonatal, 1 (OMIM: 614328) with psoriasiform, including pustular exanthema, and intestinal disease (early manifesting diarrhea).
  • LPIN2 defect: autosomal recessive mutations in the LPIN2 gene, which encodes the phosphatidate phosphatase LPIN2. The LPIN2 gene is located on chromosome 18p11.31. This gene is thought to play a role in normal adipose tissue development and possibly in human triglyceride metabolism. Mutations in this gene are associated with chronic recurrent multifocal osteomyelitis, dyserythropoietic anemia (CRMO/Majeedsyndrome ; OMIM: 609628 ) with anemia requiring transfusion, and inconstantly with Sweet syndrome.
  • IL1RN defect: autosomal recessive mutations in the IL1RN gene (IL1RN stands for "Interleukin 1 Receptor Antagonist") which is localized on chromosome 2q14.1 and encodes interleukin 1 receptor antagonist. This mutation allows uncontrolled function of IL-1. Clinically, this inflammatory syndrome(DIRA/Deficiency of IL-1 Receptor Antagonist) is characterized with neonatal onset sterile multifocal osteomyelitis, with periostitis and recurrent (exanthematous) pustulosis (Osteomyelitis, Sterile Multifocal, with Periostitis and Pustulosis/ OMPP).
  • IL36RN defect: autosomal recessive mutations in the IL36RN gene (IL36RN stands for "Interleukin 36 Receptor Antagonist") which is located on chromosome 2q14.1 and encodes interleukin 36 receptor antagonist. Mutations in the IL36RN gene lead to an increase in IL-8 synthesis and to the clinical picture: DITRA (deficiency of IL-36 receptor antagonist). This is characterized by generalized pustular psoriasis (OMIM: 614204).
  • SLC29A3 defect: AR/mutations in the SLC29A3 gene (SLC29A3 stands for "Solute Carrier Family 29 Member 3") located on chromosome 10q22.1 lead to various complex syndromes characterized by hyperpigmentation and hypertrichosis of the skin. The SLC29A3 gene encodes a nucleoside transporter that plays a role in the cellular uptake of nucleosides, nucleobases and their related analogues. LOF mutations in the SLC29A3 gene are associated with "histiocytosis lymphadenopathy plus syndrome" and Rosai-Dorfman syndrome ; both syndromes are characterized by abnormal proliferation and function of histiocytes with different organ manifestations.
  • CARD14 mutation: AD/ mutation in CARD14 gene (CARD14 stands for "Caspase Recruitment Domain Family Member 14") which is located on chromosome 17q25.3 is associated with CAMPS "CARD14 mediated psoriasis" as well as pityriasis rubra pilaris. The CARD14 gene encodes a caspase recruitment domain-containing protein that belongs to the membrane-associated guanylate kinase (MAGUK) family. Members of this protein family are scaffold proteins involved in a variety of cellular processes, including cell adhesion, signal transduction, and control of cell polarity. The protein has been shown to specifically interact with BCL10, a protein known to act as a positive regulator of cell apoptosis and NF-kappaB activation and IL-8 production.
  • SH3BP2 mutation: autosomal dominant missense mutations in the SH3BP2 gene (SH3BP2 stands for "SH3 Domain Binding Protein 2") located on chromosome 4p16.3 are associated with the clinical picture of cherubism (CRBM; OMIM: 118400). The protein encoded by the SH3BP2 gene has an N-terminal pleckstrin homology (PH) domain, an SH3-binding proline-rich region, and a C-terminal SH2 domain. The protein binds to the SH3 domains of several proteins, including the ABL1 and SYK protein tyrosine kinases, and functions as a cytoplasmic adaptor protein to positively regulate transcriptional activity in T, natural killer (NK), and basophil cells. The ad mutation leads to hyperactivation of macrophages and NF-κB with bone degeneration in temporomandibular joints.
  • PSMB8 mutation: The PSMB8 gene (PSMB8 stands for "proteasome 20S subunit beta 8") located on chromosome 6p21.32 encodes a subunit of the immunoproteasome (see proteasome below), a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. Proteasomes are distributed at high levels in eukaryotic cells and cleave peptides in an ATP/ubiquitin-dependent process by a non-lysosomal pathway. Expression of this gene is induced by gamma interferon. An autosomal recessive or autosomal dominant mutation in the PSMB8 gene leads to the clinical picture of "CANDLE syndrome " (chronic atypical neutrophilic dermatitis with lipodystrophy) with recurrent fever, anular erythema, eyelid and lip edema, and progressive peripheral lipodystrophy via increased IFN synthesis .
  • PSMA3 mutation: The PSMA3 gene (PSMA3 stands for "Proteasome (Prosome, Macropain) Subunit, Alpha Type, 3") located on chromosome 14q23.1 encodes a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. Proteasomes are distributed at high levels in eukaryotic cells and cleave peptides in an ATP/ubiquitin-dependent process by a non-lysosomal pathway. An autosomal recessive mutation leads to panniculitis, lipodystrophy, and autoimmune hemolytic anemia via increased IFN synthesis (mechanism is as yet unknown).
  • OTULIN defect: AR/mutation in OTULIN (OTULIN stands for: OTU Deubiquitinase With Linear Linkage Specificity). Increased NF-κB activation via LUBAC, resulting in high proinflammatory cytokines with fever, diarrhea and inflammatory exanthema (see autoinflammation- panniculitis- dermatosis syndrome below).
  • TNFAIP3 defect: The TNFAIP3 gene (TNFAIP3 stands for TNF Alpha Induced Protein 3) on chromosome 6q23.3 encodes a zinc finger protein and ubiquitin-editing enzyme. Diseses exhibits both ubiquitin ligase and deubiquitinase activities, and is involved in cytokine-mediated immune and inflammatory responses. It has been shown to inhibit NF-kappa B activation and TNF-mediated apoptosis. TNFAIP3 gene expression is induced by tumor necrosis factor (TNF). Diseases associated with TNFAIP3 includeBehcet-like familialautoinflammatory syndrome 1 and primary mediastinal B-cell lymphoma.
  • ELF4 defect: DAs ELF4 gene (E74 steth for "Like ETS Transcription Factor 4") is a protein coding gene located on chromosome Xq26.1.

    The transcription activator binds to DNA sequences containing the consensus 5'-WGGA-3'. Diseases associated with ELF4 include: Autoinflammatory syndrome, familial, X-linked, Behcet-like 2

    and "Isolated growth hormone deficiency, type 3, with agammaglobulinemia".AP1S3 defect: The AP1S3 gene (AP1S3 stands for "Adaptor Related Protein Complex 1 Subunit Sigma 3") is localized to chromosome 2q36.1and encodes a component of adaptor protein complex 1 (AP-1), one of the AP complexes involved in clathrin-mediated vesicular transport from the Golgi or endosomes. Diseases associated with an autosomal recessive mutation in the AP1S3 gene include pustular psoriasis and pustulosis palmaris et plantaris.
  • ALPI defect: The ALPI gene (ALPI stands for "alkaline phosphatase, intestinal") is located on chromosome 2q37.1 and encodes intestinal alkaline phosphatase, a "digestive brush-border enzyme". The enzyme is part of the defense system of the intestinal mucosa and is thought to have a detoxification function on lipopolysaccharides. Autosomal recessive mutations in ALPI result in impaired LPS inhibition in the gut and inflammatory bowel disease. Note: there are at least four different but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue nonspecific).
  • TRIM22 mutation: The TRIM22 gene (TRIM22 stands for "Tripartite Motif Containing 22" ) is located on chromosome 11p15.4 and encodes a member of the TRIM family (tripartite motif). The TRIM motif comprises three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. This protein is localized in the cytoplasm. Its expression is induced by interferon. The protein is involved in innate immunity to various DNA and RNA viruses. An autosomal recessive mutation in this gene results in granulomatous colitis.
  • HAVCR2 mutation: The HAVCR2 gene (HAVCR2 stands for "Hepatitis A Virus Cellular Receptor 2") located on chromosome 5q33.3 encodes a protein belonging to the immunoglobulin superfamily and the TIM family of proteins. This protein is a Th1-specific cell surface protein that regulates macrophage activation, inhibits Th1-mediated autoimmune and alloimmune responses, and promotes immunological tolerance. An autosomal recessive mutation in HAVCR2 is associated with subcutaneous panniculitis-like T-cell lymphoma.

Literature
This section has been translated automatically.

  1. N.Wagner et al (2022) Pediatric Rheumatology 3rd ed. XVIII, 1011 P. 378

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

Last updated on: 23.06.2022