Phenotypes Associated with This Genotype

Genotype
MGI:3698734

• Allelic Composition: Zap70^m1Saka/Zap70^m1Saka
• Genetic Background: involves: BALB/c

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

hematopoietic system

decreased T cell proliferation ( J:86607 , J:154166 )

• proliferative response to various T cell stimulating treatments is reduced compared to controls (J:86607)

• poor proliferative responses to TCR and CD28 stimulation (J:154166)

abnormal thymus cell ratio ( J:154166 )

• significant decrease in the absolute number of CD4 and CD8 single positive subsets

• however, total thymic cellularity is only mildly decreased

abnormal thymocyte activation ( J:154166 )

• an attenuated TCR-induced increase in cytoplasmic free calcium in thymocytes and peripheral T cells

abnormal T cell differentiation ( J:86607 )

• TCR^high mature thymocytes are decreased in number and ratio compared to wild-type, while TCR^low immature cells increase in thymus

abnormal T cell selection ( J:86607 )

• thmocytes exhibit abnormal sensitivity to both positive and negative selection

abnormal T cell clonal deletion ( J:154166 )

• defective clonal deletion of Vbeta5 and Vbeta11 thymocytes from endogenous viral superantigens, Mtv-8 and Mtv-9

abnormal positive T cell selection ( J:86607 , J:154166 )

• mice show positive thymic selection of arthritogenic autoimmune T cells (J:86607)

• numbers of the HSA^lo TCRbeta^hi cells are substantially decreased in mutant mice as compared with thymocytes from wild-type mice (J:154166)

increased B cell number ( J:86607 )

• B cell numbers are relatively increased

decreased CD4-positive, alpha-beta T cell number ( J:86607 , J:154166 )

• peripheral CD4+ numbers are decreased, with relative increase in B cells (J:86607)

• absolute numbers of CD4 single positive thymocytes are profoundly reduced, and fewer mature CD4+ T cells are present in the periphery (J:154166)

decreased CD8-positive, alpha-beta T cell number ( J:86607 , J:154166 )

• peripheral CD8+ numbers are decreased, with relative increase in B cells (J:86607)

• absolute numbers of CD8 single positive thymocytes are profoundly reduced, and fewer mature CD8+ T cells are present in the periphery (J:154166)

increased memory T cell number ( J:154166 )

• increase percentages of memory CD4 + T cells

decreased regulatory T cell number ( J:154166 )

• a marked reduction in both thymic T reg cell frequency as well as absolute T reg cell numbers

increased activated T cell number ( J:154166 )

• the percentages of CD45RB^lo CD4+ T cells were increased

abnormal splenic cell ratio ( J:154166 )

• significant decrease in the absolute number of CD4 and CD8 single positive subsets

increased immunoglobulin level ( J:86607 )

• mice display severe hypergammaglobulinemia

cellular

decreased T cell proliferation ( J:86607 , J:154166 )

• proliferative response to various T cell stimulating treatments is reduced compared to controls (J:86607)

• poor proliferative responses to TCR and CD28 stimulation (J:154166)

immune system

decreased T cell proliferation ( J:86607 , J:154166 )

• proliferative response to various T cell stimulating treatments is reduced compared to controls (J:86607)

• poor proliferative responses to TCR and CD28 stimulation (J:154166)

abnormal thymus cell ratio ( J:154166 )

• significant decrease in the absolute number of CD4 and CD8 single positive subsets

• however, total thymic cellularity is only mildly decreased

abnormal thymocyte activation ( J:154166 )

• an attenuated TCR-induced increase in cytoplasmic free calcium in thymocytes and peripheral T cells

abnormal T cell differentiation ( J:86607 )

• TCR^high mature thymocytes are decreased in number and ratio compared to wild-type, while TCR^low immature cells increase in thymus

abnormal T cell selection ( J:86607 )

• thmocytes exhibit abnormal sensitivity to both positive and negative selection

abnormal T cell clonal deletion ( J:154166 )

• defective clonal deletion of Vbeta5 and Vbeta11 thymocytes from endogenous viral superantigens, Mtv-8 and Mtv-9

abnormal positive T cell selection ( J:86607 , J:154166 )

• mice show positive thymic selection of arthritogenic autoimmune T cells (J:86607)

• numbers of the HSA^lo TCRbeta^hi cells are substantially decreased in mutant mice as compared with thymocytes from wild-type mice (J:154166)

increased B cell number ( J:86607 )

• B cell numbers are relatively increased

decreased CD4-positive, alpha-beta T cell number ( J:86607 , J:154166 )

• peripheral CD4+ numbers are decreased, with relative increase in B cells (J:86607)

• absolute numbers of CD4 single positive thymocytes are profoundly reduced, and fewer mature CD4+ T cells are present in the periphery (J:154166)

decreased CD8-positive, alpha-beta T cell number ( J:86607 , J:154166 )

• peripheral CD8+ numbers are decreased, with relative increase in B cells (J:86607)

• absolute numbers of CD8 single positive thymocytes are profoundly reduced, and fewer mature CD8+ T cells are present in the periphery (J:154166)

increased memory T cell number ( J:154166 )

• increase percentages of memory CD4 + T cells

decreased regulatory T cell number ( J:154166 )

• a marked reduction in both thymic T reg cell frequency as well as absolute T reg cell numbers

increased activated T cell number ( J:154166 )

• the percentages of CD45RB^lo CD4+ T cells were increased

abnormal splenic cell ratio ( J:154166 )

• significant decrease in the absolute number of CD4 and CD8 single positive subsets

increased immunoglobulin level ( J:86607 )

• mice display severe hypergammaglobulinemia

abnormal lymph node cell ratio ( J:154166 )

• significant decrease in the absolute number of CD4 and CD8 single positive subsets

increased interleukin-17 secretion ( J:154166 )

• the percentages of IL-17 producing cells are 15- fold higher than in the wild-type controls

decreased interleukin-2 secretion ( J:154166 )

• IL-2 production after CD3 stimulation was greatly reduced in mutant mice

increased susceptibility to induced arthritis ( J:154166 )

• mice develop Rheumatoid Factor antibodies after zymosan challenge

increased autoantibody level ( J:86607 )

• mice develop high titres of rheumatoid factor, autoantibodies to type II collagen, heat shock protein-70 and high levels of circulating immune complexes

rheumatoid arthritis ( J:86607 )

• by ~2 months of age

chronic joint inflammation ( J:86607 )

• swollen joints showed severe synovitis with subsynovial neutrophil, lymphocyte, macrophage and plasma cell infiltration

lung inflammation ( J:86607 )

• pneumonitis with perivascular and peribronchiolar cellular infiltration (extra-articular manifestation of arthritis) affects >90% of mutants by 6 months of age

skeleton

joint swelling ( J:86607 )

• swelling with hyperaemia is evident at 2 month of age at interphalangeal joints of forepaws, then proceeding symmetrically to other finger joints of fore- and hindpaws and wrists and ankles

• severe synovitis with inflammatory cell infiltration is observed in swollen joints, and increases in severity with age

increased susceptibility to induced arthritis ( J:154166 )

• mice develop Rheumatoid Factor antibodies after zymosan challenge

rheumatoid arthritis ( J:86607 )

• by ~2 months of age

chronic joint inflammation ( J:86607 )

• swollen joints showed severe synovitis with subsynovial neutrophil, lymphocyte, macrophage and plasma cell infiltration

osteoporosis ( J:86607 )

• by 8-12 months of age

fused joints ( J:86607 )

• at 8-12 months of age, fusion of subchondral bones (wrist and ankle joints) is observed radiographically

joint dislocation ( J:86607 )

• dislocation of wrist and ankle joints is observed radiographically at 8-12 months of age

respiratory system

lung inflammation ( J:86607 )

• pneumonitis with perivascular and peribronchiolar cellular infiltration (extra-articular manifestation of arthritis) affects >90% of mutants by 6 months of age

integument

mixed cellular infiltration to dermis ( J:86607 )

• >90% of mice show infiltration of inflammatory cells to skin by 6 months of age

endocrine/exocrine glands

abnormal thymus cell ratio ( J:154166 )

• significant decrease in the absolute number of CD4 and CD8 single positive subsets

• however, total thymic cellularity is only mildly decreased

abnormal thymocyte activation ( J:154166 )

• an attenuated TCR-induced increase in cytoplasmic free calcium in thymocytes and peripheral T cells

homeostasis/metabolism

joint swelling ( J:86607 )

• swelling with hyperaemia is evident at 2 month of age at interphalangeal joints of forepaws, then proceeding symmetrically to other finger joints of fore- and hindpaws and wrists and ankles

• severe synovitis with inflammatory cell infiltration is observed in swollen joints, and increases in severity with age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
rheumatoid arthritis		DOID:7148	OMIM:180300	J:86607