A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70

Chan, Alice; Punwani, Divya; Kadlecek, Theresa A.; Cowan, Morton J.; Olson, Jean L.; Mathes, Erin F.; Sunderam, Uma; Fu, Shu Man; Srinivasan, R.; Kuriyan, John; Brenner, Steven E.; Weiss, Arthur; Puck, Jennifer M.

doi:10.1084/jem.20150888

Cited by 86 publications

(89 citation statements)

References 50 publications

(80 reference statements)

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“…Efforts have been made in humans to determine whether any mutation of ZAP70 can be causative of autoimmune disease such as RA. A recent report has indeed shown that individuals with compound heterozygous missense mutations of R192W in the C‐SH2 domain and R360P in the catalytic domain developed bullous pemphigoid, colitis, and nephrotic syndrome within their first year of life . The former mutation was hypomorphic affecting the binding to CD3ζ, the latter making ZAP‐70 weakly hyper‐reactive by disrupting auto‐inhibitory mechanisms.…”

Section: Autoimmunity Caused By Impaired Tcr‐proximal Signalingmentioning

confidence: 99%

“…A recent report has indeed shown that individuals with compound heterozygous missense mutations of R192W in the C-SH2 domain and R360P in the catalytic domain developed bullous pemphigoid, colitis, and nephrotic syndrome within their first year of life. 25 The former mutation was hypomorphic affecting the binding to CD3ζ, the latter making ZAP-70 weakly hyper-reactive by disrupting auto-inhibitory mechanisms. Thus, certain ZAP70 mutations can be causative of immunodeficiency and autoimmune disease in humans.…”

Section: Zap70 Mutations In Humans As a Cause Of Immunodeficiency Amentioning

confidence: 99%

“…For example, deficiency or mutations of the genes encoding TCR‐proximal signal transduction molecules, such as CD3ζ, lymphocyte protein tyrosine kinase (Lck), linker for activation of T cells (LAT), Src‐like adapter protein (SLAP), protein tyrosine phosphatase non‐receptor type 22 (Ptpn22), and ζ‐chain–associated protein kinase (Zap‐70), cause immunodeficiency, systemic inflammatory diseases, or both, in mice (Table ). While the immunodeficient phenotype of LAT‐, Lck‐, or Zap‐70‐deficiency is due to developmental arrest of thymocytes, , T cell–mediated or T cell–dependent autoimmunity due to mutations of the CD3ζ, LAT, or Zap‐70 gene is not much clear in how the mutations lead to autoimmunity . In humans, recent genome‐wide association studies (GWASs) have identified the C1858T variant of PTPN22, which inhibits TCR‐proximal signaling molecules such as Lck and ZAP‐70, as a significant genetic risk factor for several autoimmune diseases including RA .…”

Section: Introductionmentioning

confidence: 99%

“…While the immunodeficient phenotype of LAT-, Lck-, or Zap-70-deficiency is due to developmental arrest of thymocytes, [11][12][13][14][15]16,17 T cell-mediated or T cell-dependent autoimmunity due to mutations of the CD3ζ, LAT, or Zap-70 gene is not much clear in how the mutations lead to autoimmunity. [18][19][20][21][22][23][24][25] In humans, recent genome-wide association studies (GWASs) have identified the C1858T variant of PTPN22, which inhibits TCR-proximal signaling molecules such as Lck and ZAP-70, as a significant genetic risk factor for several autoimmune diseases including RA. [26][27][28][29] Among these various genetic alterations affecting T cell development and function, a Zap70 gene mutation found in SKG mice is unique in that it predominantly causes T cell-mediated autoimmune arthritis, enabling us to ask how the primary anomaly in T cells, not in tissue resident cells in the joint, causes autoimmune disease clinically and immunologically resembling human RA.…”

Section: Introductionmentioning

confidence: 99%

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Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

Takeuchi

Hirota

Sakaguchi

2020

Immunological Reviews

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Mutations of the genes encoding T‐cell receptor (TCR)‐proximal signaling molecules, such as ZAP‐70, can be causative of immunological diseases ranging from T‐cell immunodeficiency to T‐cell–mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap‐70 gene, spontaneously develop T‐cell–mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap‐70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self‐peptides/MHC complexes, shifting self‐reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self‐reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self‐peptide/MHC complexes on antigen‐presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL‐6 to drive the arthritogenic T cells to differentiate into arthritogenic T‐helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte‐macrophage colony‐stimulating factor‐secreting effector Th17 cells, mediating chronic bone‐destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune‐suppressing Treg cells to treat and prevent RA.

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Section: Autoimmunity Caused By Impaired Tcr‐proximal Signalingmentioning

confidence: 99%

Section: Zap70 Mutations In Humans As a Cause Of Immunodeficiency Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

Takeuchi

Hirota

Sakaguchi

2020

Immunological Reviews

View full text Add to dashboard Cite

show abstract

“…The former mutation results in decreased binding to phospho-CD3, whereas the latter mutation reduces an autoinhibitory mechanism. 48 These mutations that alter TCR signalling thresholds cause autoimmune diseases as phenotypically demonstrated by uncontrollable bullous pemphigoid, colitis and proteinuria. 48 ZAP-70 is structurally composed of two SH2 domains separated by a so-called interdomain A.…”

Section: Zap-70mentioning

confidence: 99%

Selected signalling proteins recruited to the T‐cell receptor–CD3 complex

2017

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SummaryThe T-cell receptor (TCR)-CD3 complex, expressed on T cells, determines the outcome of a T-cell response. It consists of the TCR-ab heterodimer and the non-covalently associated signalling dimers of CD3ec, CD3ed and CD3ff. TCR-ab binds specifically to a cognate peptide antigen bound to an MHC molecule, whereas the CD3 subunits transmit the signal into the cytosol to activate signalling events. Recruitment of proteins to specialized localizations is one mechanism to regulate activation and termination of signalling. In the last 25 years a large number of signalling molecules recruited to the TCR-CD3 complex upon antigen binding to TCR-ab have been described. Here, we review knowledge about five of those interaction partners: Lck, ZAP-70, Nck, WASP and Numb. Some of these proteins have been targeted in the development of immunomodulatory drugs aiming to treat patients with autoimmune diseases and organ transplants.

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Determination of disease phenotypes and pathogenic variants from exome sequence data in the CAGI 4 gene panel challenge

et al. 2017

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The use of gene panel sequence for diagnostic and prognostic testing is now widespread, but there are so far few objective tests of methods to interpret these data. We describe the design and implementation of a gene panel sequencing data analysis pipeline (VarP) and its assessment in a CAGI4 community experiment. The method was applied to clinical gene panel sequencing data of 106 patients, with the goal of determining which of 14 disease classes each patient has and the corresponding causative variant(s). The disease class was correctly identified for 36 cases, including 10 where the original clinical pipeline did not find causative variants. For a further seven cases, we found strong evidence of an alternative disease to that tested. Many of the potentially causative variants are missense, with no previous association with disease, and these proved the hardest to correctly assign pathogenicity or otherwise. Post analysis showed that three-dimensional structure data could have helped for up to half of these cases. Over-reliance on HGMD annotation led to a number of incorrect disease assignments. We used a largely ad hoc method to assign probabilities of pathogenicity for each variant, and there is much work still to be done in this area.

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A novel human autoimmune syndrome caused by combined hypomorphic and activating mutations in ZAP-70

Abstract: Chan et al. describe a combination of alleles with hypomorphic and activating mutations in the T cell signaling molecule ZAP-70 in a patient with autoimmunity.

Cited by 86 publications

References 50 publications

Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

Impaired T cell receptor signaling and development of T cell–mediated autoimmune arthritis

Selected signalling proteins recruited to the T‐cell receptor–CD3 complex

Determination of disease phenotypes and pathogenic variants from exome sequence data in the CAGI 4 gene panel challenge

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