• Background Sensitivity: while mutants on the C57BL/6 background develop lupus-like disease, they fail to develop Sjogrens syndrome-like disease as seen in the BALB/c background, showing no signs of enlarged submaxillary glands or elevated serum anti-SSB/La IgG autoantibodies (J:187766)

• mutants exhibit a skewing in the repertoire from T1 to T2/T3 B cells resulting in ratios of T2:T1 and T3:T1 B cells that are increased compared to wild-type mice

• number of B cells in the spleen shows a trend toward a statistical increase compared to controls

• however, number of T cells in the spleen is similar to wild-type

• 16-18 week old mutants exhibit significantly increased numbers of total immature AA4.1+B220+ B cells

• mutants exhibit elevated levels of marginal zone B cells

• however, no increase in the number of follicular mature B cells is seen

• in 32-40 week old mutants

• in 32-40 week old mutants

• in 32-40 week old mutants

• increase in cervical lymph node weight and cellularity in 32-40 week old mutants

• increase in cervical lymph node weight and cellularity in 32-40 week old mutants

• 28-32 week old mutants exhibit hypergammaglobulinemia

• however levels of IgM are normal

• 28-32 week old mutants exhibit elevated levels of serum anti-nuclear autoantibodies (anti-chromatin IgG, anti-histone IgG, and anti-dsDNA IgG)

• mutants exhibit a skewing in the repertoire from T1 to T2/T3 B cells resulting in ratios of T2:T1 and T3:T1 B cells that are increased compared to wild-type mice

• number of B cells in the spleen shows a trend toward a statistical increase compared to controls

• however, number of T cells in the spleen is similar to wild-type

• 16-18 week old mutants exhibit significantly increased numbers of total immature AA4.1+B220+ B cells

• mutants exhibit elevated levels of marginal zone B cells

• however, no increase in the number of follicular mature B cells is seen

• in 32-40 week old mutants

• in 32-40 week old mutants

• in 32-40 week old mutants

• mutants exhibit elevated IgG deposition within the kidney glomeruli

• however, renal failure is not seen in mutants up to 12 months of age

• kidneys show occasional obstruction of the capillary lumina

• kidneys show moderate hypercellularity of the glomerular mesangium and occasional obstruction of the capillary lumina, however no signs of mononuclear cell infiltrates or signs of tubulointerstitial disease

• kidneys show occasional obstruction of the capillary lumina

• mutants exhibit a skewing in the repertoire from T1 to T2/T3 B cells resulting in ratios of T2:T1 and T3:T1 B cells that are increased compared to wild-type mice

• 16-18 week old mutants exhibit significantly increased numbers of total immature AA4.1+B220+ B cells

• mutants begin to die around 4 months of age and by 12 months of age, about 83% mutants are dead

• lymph nodes proximal to the submaxillary glands are greatly enlarged

• mutants, but not wild-type mice, develop anti-SSA/Ro and anti-SSB/La autoantibodies in response to recombinant SSA/Ro and SSB/La antigens

• lymphocyte infiltration in lacrimal, parotid and submaxillary glands; most infiltrates are in the perivascular or periductal areas of the glands

• lymphocyte infiltration in submandibular glands

• lymphocyte infiltration in lacrimal glands

• lacrimal glands are infiltrated by B220+ B cells and T cells

• some mutants develop skin lesions around the eyes due to excessive scratching of affected eyes

• both males and females exhibit difficulties in maintaining fully opened eyelids beginning around 3 weeks of age due to inflammation

• mutants at 8-12 months of age exhibit lymphocyte infiltration in the kidney, including the glomeruli

• presence of anti-DNA autoantibodies and IgG complex in glomeruli, indicating development of glomerulonephritis

• mutants exhibit reduced flow rate of saliva production

• lymphocyte infiltration in parotid glands

• enlarged submaxillary glands

• lymphocyte infiltration in submandibular glands

• mutants at 8-12 months of age exhibit lymphocyte infiltration in the kidney, including the glomeruli

• presence of anti-DNA autoantibodies and IgG complex in glomeruli, indicating development of glomerulonephritis

• mouth inflammation

• mutants exhibit reduced flow rate of saliva production

• mutants exhibit reduced flow rate of saliva production

• lymphocyte infiltration in submandibular glands

• exocrine glands are infiltrated by large number of B and T cells

• lymphocyte infiltration in parotid glands

• enlarged submaxillary glands

• lymphocyte infiltration in lacrimal glands

• lacrimal glands are infiltrated by B220+ B cells and T cells

• lymphocyte infiltration in lacrimal glands

• lacrimal glands are infiltrated by B220+ B cells and T cells

• some mutants develop skin lesions around the eyes due to excessive scratching of affected eyes

• both males and females exhibit difficulties in maintaining fully opened eyelids beginning around 3 weeks of age due to inflammation

• the number of dendritic cells is increased in the spleen

• the total splenic B cell population is increased however the proportions of different B cell stages are the same as in wild-type littermates

• the density of B cell zones is increased

• the number of dendritic cells is increased in the spleen

• the total splenic B cell population is increased however the proportions of different B cell stages are the same as in wild-type littermates

• the density of B cell zones is increased

• at 3 weeks of age the lymph nodes are enlarged from lymphoid hyperplasia, increased germinal centers, and accumulation of plasma cells

• IgG subclasses except for IgG3 are increased

• both T cell dependent and independent antigens elicit increased antigen-specific responses

• anti-dsDNA IgG antibodies are detected

• anti-histone IgG antibodies are detected

• anti-ssDNA IgG antibodies are detected

• inflammation is seen in multiple tissues including the skin

• upper respiratory airway inflammation is seen

• upper respiratory airway inflammation is seen

• the number of dendritic cells is increased in the spleen, this is less severe than in Act1 null mice

• the total splenic B cell population is increased however the proportions of different B cell stages are the same as in wild-type littermates

• this is less severe than in Act1 null mice

• this is less severe than in Act1 null mice

• the number of dendritic cells is increased in the spleen, this is less severe than in Act1 null mice

• the total splenic B cell population is increased however the proportions of different B cell stages are the same as in wild-type littermates

• this is less severe than in Act1 null mice

• this is less severe than in Act1 null mice

• this is less severe than in Act1 null mice

• this is less severe than in Act1 null mice

• triple mutants exhibit reduced lupus-like phenotypes compared to Traf3ip2 single homozygotes, with normal spleen weight and cellularity, normal B cell numbers (B cell numbers however are decreased compared to Tcrb and Tcrd double homozygous mutants), normal cervical lymph node weight and cellularity, significantly less total IgG antibodies and anti-nuclear antigen specific IgG autoantibodies, and no IgG deposition in the kidney glomeruli (J:187766)

• ratios of T2:T1 and T3:T1 B cells are increased compared to wild-type mice

• 16-18 week old mutants exhibit a trend toward an increase in numbers of immature B cells

• mutants exhibit increased levels of marginal zone B cells compared to wild-type mice, however levels are similar to that seen in Traf3ip2 single homozygotes or to Tcrb and Tcrd double homozygous mutants, indicating no further increase in levels

• decrease in the number of T cells in the spleen compared to wild-type mice and Traf3ip2 single homozygotes

• mutants develop significantly less total IgG antibodies (IgG, IgG1, IgG2c) and anti-nuclear antigen specific IgG autoantibodies than Traf3ip2 single homozygotes

• the IgG deposition within the kidney glomeruli that is seen in Traf3ip2 single homozygotes is not seen in triple mutants

• mutants exhibit elevated levels of IgM deposition within kidney glomeruli

• serum levels of anti-chromatin IgM, anti-histone IgM, and anti-dsDNA Igm are elevated in triple mutants compared to Traf3ip2 single homozygotes

• serum levels of anti-chromatin IgM are elevated in triple mutants compared to Traf3ip2 single homozygotes

• serum levels anti-dsDNA IgM are elevated in triple mutants compared to Traf3ip2 single homozygotes

• serum levels of anti-histone IgM are elevated in triple mutants compared to Traf3ip2 single homozygotes

• ratios of T2:T1 and T3:T1 B cells are increased compared to wild-type mice

• 16-18 week old mutants exhibit a trend toward an increase in numbers of immature B cells

• mutants exhibit increased levels of marginal zone B cells compared to wild-type mice, however levels are similar to that seen in Traf3ip2 single homozygotes or to Tcrb and Tcrd double homozygous mutants, indicating no further increase in levels

• decrease in the number of T cells in the spleen compared to wild-type mice and Traf3ip2 single homozygotes

• kidneys show occasional obstruction of the capillary lumina

• ratios of T2:T1 and T3:T1 B cells are increased compared to wild-type mice

• 16-18 week old mutants exhibit a trend toward an increase in numbers of immature B cells

• mutants exhibit elevated levels of IgM deposition within kidney glomeruli

• kidneys show occasional obstruction of the capillary lumina

• kidneys show moderate hypercellularity of the glomerular mesangium and occasional obstruction of the capillary lumina, however no signs of mononuclear cell infiltrates or signs of tubulointerstitial disease

• double mutants exhibit an increase in peripheral B cell populations compared to Cd40 single homozygotes

• double mutants exhibit an increase in peripheral B cell populations compared to Cd40 single homozygotes

• double mutants exhibit an increase in peripheral B cell populations compared to Cd40 single homozygotes

• enlargement of the spleen is reduced compared to Traf3ip2 single homozygotes

• immunoglobulin levels are normal unlike in Traf3ip2 single homozygotes

• double mutants do not exhibit production of anti-SSA/Ro and anti-SSB/La autoantibodies in response to recombinant SSA/Ro and SSB/La antigens, as seen in Traf3ip2 single homozygotes (J:138560)

• double mutants exhibit an increase in peripheral B cell populations compared to Cd40 single homozygotes

• double mutants exhibit an increase in peripheral B cell populations compared to Cd40 single homozygotes

• double mutants exhibit an increase in peripheral B cell populations compared to Cd40 single homozygotes

• enlargement of the spleen is reduced compared to Traf3ip2 single homozygotes

• immunoglobulin levels are normal unlike in Traf3ip2 single homozygotes

• enlargement of the lymph nodes is reduced compared to Traf3ip2 single homozygotes

• Tnfsf13b (BAFF) stimulation results in enhanced B cell survival compared to single Cd40 mutants

• double mutants exhibit an increase in peripheral B cell populations compared to Cd40 single homozygotes

• total splenic B cells, transitional B cells and follicular B cells are reduced in the spleen

• total number of mature B cells is reduced

• enlargement of the spleen is reduced compared to Traf3ip2 single homozygotes

• immunoglobulin levels are normal unlike in Traf3ip2 single homozygotes

• total splenic B cells, transitional B cells and follicular B cells are reduced in the spleen

• total number of mature B cells is reduced

• enlargement of the spleen is reduced compared to Traf3ip2 single homozygotes

• immunoglobulin levels are normal unlike in Traf3ip2 single homozygotes

• enlargement of the lymph nodes is reduced compared to Traf3ip2 single homozygotes

• mutants develop anti-SSA/Ro and anti-SSB/La autoantibodies in response to recombinant SSA/Ro and SSB/La antigens, although to a lower level than in Traf3ip2 single homozygotes due to the low number of B cells, but higher levels than in Tnfsf13b single homozygotes