Skip to main content
. Author manuscript; available in PMC: 2020 May 1.
Published in final edited form as: Trends Mol Med. 2019 Mar 18;25(5):428–443. doi: 10.1016/j.molmed.2019.02.002

Table 1.

(Key Table): Mouse models with altered E3 ligase activity and autoimmune phenotypes

E3 ligase Mouse model
(genetic background)		 Autoimmune phenotypes Immune cell phenotype Ref
T cells
GRAIL Rnf128−/−
(C57BL/6 × 129 or
C57BL/6)		 - Spontaneous autoimmunity in
aged mice; splenomegaly,
increased mesenteric lymph
nodes, lymphocyte infiltration
in multiple organs; autoantibody
production;
- Enhanced experimental
autoimmunity upon transfer
of Rnf128−/−CD4+ T cells in
Rag1−/− mice		 - T cell activation
(independent of
costimulation)
- Treg show impaired
suppressor
function		 [24]
Cbl-b CBLB−/−
(C57BL/6)		 Spontaneous autoimmunity in
aged mice (6 months);
autoantibody production,
infiltration of activated T and B
lymphocytes into multiple
organs; parenchymal damage		 - B cells show enhanced
proliferation upon
stimulation;
- T cell activation
(independent of
costimulation)		 [32]
CBLB−/−
(C57BL/6 – 129)		 - No spontaneous
autoimmunity (8 month);
- High susceptibility to EAE		 - T cell activation
independent of
costimulation		 [31]
CBLBC373A
(KI of E3 ligase
defective mutant)
(C57BL/6)		 Spontaneous autoimmunity;
autoantibody production;
infiltration of mononuclear cells
into multiple organs		 - T cell activation
independent of
costimulation		 [74]
ITCH Itchy mice (aH18
agouti mice)
(C57BL/6J or
JU/Ct-C,A)		 Itchy JU/Ct-C,A (age 3–4 months):
- intestinal infiltration of
inflammatory and
mononuclear cells; rare
scarring of skin due to
scratching
Itchy C57BL/6J (lethality between
4–6 months):
- no intestinal lesions but
airway inflammation;
enlarged lymph nodes, spleen
and thymus; inflamed
ulcerated skin; increased
serum IgE and IgG1		 C57BL/6J background:
- enhanced TH2
differentiation;
- TH2 resistance to
tolerance
- diminished
generation of
inducible Treg		 [26, 33, 126–128]
Itchf/lFoxp3Cre - Spontaneous autoimmunity
and lymphoproliferative
disease (6 weeks):
enlargement and higher
cellularity of peripheral
lymphoid organs; massive
infiltration of multiple organs;
- exacerbated airway inflammation
upon experimental
challenge		 - Treg acquire TH2
properties
- enhanced TH2
differentiation from
naive T cells		 [49]
Cbl-b
+
ITCH 		CBLB−/−ITCH−/− DKO
(C57BL/6)		 Spontaneous autoimmunity (6–
12 weeks):
Enlarged spleen, lymph nodes;
massive lymphocyte infiltration
in multiple organs; high
concentration of autoantibodies		 - CD4+ T cells
(independent of
costimulation)		 [129]
WWP2
+
ITCH 		Wwp2−/−
:Itchf/f:Cd4-cre
(C57BL/6)		 Spontaneous autoimmunity:
autoantibody production,
inflammatory phenotypes,
myeloid infiltration of lungs;
elevated serum IL6		 - enhanced TH2
differentiation;
- elevated IL4
production		 [130]
Roquin1 sanroque mice
(Rc3h1M199R)
(C57BL/6 and CBA)		 Spontaneous autoimmunity:
SLE-like glomerulonephritis and
deposition of immune
complexes; necrotizing
hematitis; anemia; enlarged
spleen and lymph nodes;
spontaneous GC formation in
spleen; plasma cell infiltration in
multiple organs; autoantibodies		 - CD4+ T cells prone
to differentiate into
TFH cells		 [131]
Roquin1
+
Roquin2 		Rc3h1f/f:
Rc3h2f/f:Lck-cre
(RING-domain deleted
cDKO; T cell)		 elevated TFH formation,
and increase in GC B cells
upon immunization from
8 to 12 weeks		 [132]
Roquin1
+
Roquin2 		Rc3h1f/f:Rc3h2f/f:
Cd4-cre (T cell cKO)		 - lymphadenopathy;
splenomegaly;
- no spontaneous GC formation;
no autoantibodies;
- perturbed splenic architecture		 - Activation of CD4
and CD8 T cells
- Increase in Treg
numbers
- increase in TFH cells
- increase in GC B
cells		 [133]
TRAF6 TRAF6f/f:Cd4-cre
mixed background
(C57BL/6 – 129)		 spontaneous autoimmunity:
multi-organ infiltration with B
and CD4 T cells, increased
autoantibodies		 - CD4 T cells resistant
to suppression by
Treg
- proliferation
independent of
CD28 costimulation		 [134]
Peli1 Peli1−/− (C57BL/6) - Spontaneous autoimmunity (6
months): T and B cell
infiltration of kidney, liver, lung;
autoantibodies; immune
complexes in kidney glomeruli;
- Increased EAE upon T cell
transfer in Rag1−/− mice		 - T cell activation
independent of
costimulation
- resistant to Tregmediated
suppression		 [135]
B cells
Peli1 Peli1−/−
(C57BL/6)		 increased severity of lupus-like
disease in experimental lupus
(BM12) model		 - B cell proliferation
in response to CD40,
BAFF
- T cell-dependent
antibody response		 [124]
TRAF3 Traf3f/f:Cd19-cre
(C57BL/6 – 129)		 spontaneous autoimmunity (12
months):
autoantibodies (from 10wks on);
lymphocyte infiltration of kidney,
liver; glomerular immune
complex deposits		 - B cell survival
- T cell-dependent
antibody response		 [136]
A20 Tnfaip3f/f:Cd19-
cre		 Spontaneous autoimmunity:
- SLE-like: increase in GC B cell
numbers, autoantibodies,
glomerular immune complex
deposits
OR
- inflammatory autoimmune
syndrome, splenomegaly,
plasma cell hyperplasia, IgG
autoantibodies		 B cell proliferation and
survival		 Reviewed
in [137]
Innate immune cells
A20 Tnfaip3f/f:Cd11ccre
(C57BL/6)		 Spontaneous autoimmunity:
- SLE-like autoimmunity
- IBD-like autoimmunity:
lymphocyte-dependent colitis,
seronegative ankylosing
arthritis, enthesitis		 increased survival and
DC hyper-responsiveness		 Reviewed
in [137]
Tnfaip3f/f:LysMcre
(C57BL/6)		 Spontaneous destructive arthritis increased cytokine
production by
macrophages		 Reviewed
in [137]
Peli1 Peli1−/−
(C57BL/6 – 129/Sv)		 Reduced severity of EAE Microglia activation [138]

EAE: experimental autoimmune encephalomyelitis; KO: knockout; DKO: double KO; cKO: conditional KO; TFH: T follicular helper cell; GC: germinal center; Teff: effector T cells; Treg: regulatory T cells; cDKO: conditional DKO; NA: not applicable; IBD: inflammatory bowel disease; SLE: systemic lupus erythematosus