| Features . | Mice . | Humans . | ||||
|---|---|---|---|---|---|---|
| . | ICOSLG deficiency . | ICOS deficiency . | NIK (MAP3K14) deficiency . | ICOSLG deficiency . | ICOS deficiency . | NIK (MAP3K14) deficiency . |
| Infections | Recurrent respiratory tract infections | Recurrent respiratory tract infections | Recurrent respiratory tract infections | |||
| Intestinal infections (Campylobacter) | Intestinal infections (Campylobacter, Salmonella norovirus, adenovirus, Cryptosporidium) | Intestinal infections (Cryptosporidium; CMV) | ||||
| Skin abscesses | Osteomyelitis with BCG | |||||
| Herpesviridae-related infections | Herpesviridae-related infections; recurrent HSV (labialis, keratitis, genital), CMV, HHV6 | |||||
| HPV | HPV: warts, cancer | |||||
| Pneumocystis jiroveci pneumonia | ||||||
| Other salient clinical features | Intermittent chronic diarrhea of unclear etiology (no evidence of infectious or inflammatory bowel disease) | Autoimmunity: RA, IBD, interstitial pneumonitis, psoriasis | Granulomatous hepatitis (possibly related to disseminated BCG) | |||
| Splenomegaly | Splenomegaly | |||||
| Dentigerous cyst | Granulomatous skin diseases | |||||
| Cytopenia; neutropenia; thrombocytopenia (2/15 patients each) | ||||||
| Cancer: HPV vulva; LGL-T; SCC | ||||||
| Immunoglobulins | Hypogammaglobulinemia of IgG, IgA, IgM | Hypogammaglobulinemia of IgG and IgA; some with low-normal IgM | Hypogammaglobulinemia of IgG, IgA; IgM low/normal/elevated | |||
| Baseline | ↓ IgG1 | ↓ IgG1 | Normal levels of IgG, IgM | |||
| ↓ IgG2a, IgG2b, IgA | ↓ IgE | ↓ IgA | ||||
| (Some mouse models had ↓ IgG2) | Normal levels of IgG1, IgG2a | |||||
| ↓ IgG2b, IgG3 | ||||||
| Response to vaccination | Intact response to T cell–independent antigen (based on IgM and IgG3 response to trinitrophenol-Ficoll) | Intact response to T cell–independent antigen (based on IgM and IgG3 response to trinitrophenol-Ficoll) | Poor (nearly absent) response to ovalbumin immunization | |||
| ↓ T cell–dependent responses (based on ↓ IgG1, ↓ IgE) | ↓ T cell–dependent responses (based on ↓ IgG1, ↓ IgG2a, ↓ IgE) | |||||
| Lymphocytes | No effect on T or B cell development from thymus or bone marrow | No effect on T or B cell development from thymus or bone marrow | Thymus: no effect on T cells | Circulating absolute T cell counts: decreased | Circulating absolute T cell counts: normal | Circulating absolute T cell counts: normal |
| Circulating CD4+ T cell subset: decreased | Circulating CD4+ T cell subset: variable | Circulating CD4+ T cell subset: normal | ||||
| No effect on overall composition of mature B and T cell subsets in spleen | No effect on overall composition of mature B and T cell subsets in spleen | Spleen: no effect on T cells; decreased B220+ IgM+ cells | Circulating CD8+ T cell subset: decreased | Circulating CD8+ T cell subset: variable | Circulating CD8+ T cell subset: normal | |
| Memory T cell counts: decreased | Memory T cell counts: variable | Memory T cell counts: normal | ||||
| Bone marrow: increased B220+ CD25+ and B220+ CD43− | Circulating Tfh (CD4+ CXCR5+ CD45RA): low–normal | Reduction in circulating Tfh (defined as CD4+ CXCR5+ CD45RA−) | Reduction in circulating Tfh (CD4+ CXCR5+ CD45RA−) | |||
| T reg cells: normal | T reg cells: normal | T reg cells: normal | ||||
| B cell counts: decreased in childhood; intermittently within reference range in adulthood | B cell counts: normal when diagnosed in childhood; decreased when diagnosed in adulthood | B cell counts: decreased | ||||
| Circulating naive B cells: increased | Circulating naive B cells: high (children); decreased (adults) | Circulating naive B cells: high (children) | ||||
| Circulating switched memory B cell cells: decreased | Circulating switched memory B cell cells: decreased | Circulating switched memory B cell cells: decreased | ||||
| NK cell counts: decreased | ||||||
| Lymphoid organs | ↓ number and size of GC formation | ↓ number and size of GC formation | Absent lymph nodes; abnormal lymphoid architecture in thymus and spleen | |||
| Myeloid cells | Not reported | Not reported | ↓ CD11b+ monocytes in spleen | Progressive neutropenia | Neutropenia (n = 2) | Not reported |
| Features . | Mice . | Humans . | ||||
|---|---|---|---|---|---|---|
| . | ICOSLG deficiency . | ICOS deficiency . | NIK (MAP3K14) deficiency . | ICOSLG deficiency . | ICOS deficiency . | NIK (MAP3K14) deficiency . |
| Infections | Recurrent respiratory tract infections | Recurrent respiratory tract infections | Recurrent respiratory tract infections | |||
| Intestinal infections (Campylobacter) | Intestinal infections (Campylobacter, Salmonella norovirus, adenovirus, Cryptosporidium) | Intestinal infections (Cryptosporidium; CMV) | ||||
| Skin abscesses | Osteomyelitis with BCG | |||||
| Herpesviridae-related infections | Herpesviridae-related infections; recurrent HSV (labialis, keratitis, genital), CMV, HHV6 | |||||
| HPV | HPV: warts, cancer | |||||
| Pneumocystis jiroveci pneumonia | ||||||
| Other salient clinical features | Intermittent chronic diarrhea of unclear etiology (no evidence of infectious or inflammatory bowel disease) | Autoimmunity: RA, IBD, interstitial pneumonitis, psoriasis | Granulomatous hepatitis (possibly related to disseminated BCG) | |||
| Splenomegaly | Splenomegaly | |||||
| Dentigerous cyst | Granulomatous skin diseases | |||||
| Cytopenia; neutropenia; thrombocytopenia (2/15 patients each) | ||||||
| Cancer: HPV vulva; LGL-T; SCC | ||||||
| Immunoglobulins | Hypogammaglobulinemia of IgG, IgA, IgM | Hypogammaglobulinemia of IgG and IgA; some with low-normal IgM | Hypogammaglobulinemia of IgG, IgA; IgM low/normal/elevated | |||
| Baseline | ↓ IgG1 | ↓ IgG1 | Normal levels of IgG, IgM | |||
| ↓ IgG2a, IgG2b, IgA | ↓ IgE | ↓ IgA | ||||
| (Some mouse models had ↓ IgG2) | Normal levels of IgG1, IgG2a | |||||
| ↓ IgG2b, IgG3 | ||||||
| Response to vaccination | Intact response to T cell–independent antigen (based on IgM and IgG3 response to trinitrophenol-Ficoll) | Intact response to T cell–independent antigen (based on IgM and IgG3 response to trinitrophenol-Ficoll) | Poor (nearly absent) response to ovalbumin immunization | |||
| ↓ T cell–dependent responses (based on ↓ IgG1, ↓ IgE) | ↓ T cell–dependent responses (based on ↓ IgG1, ↓ IgG2a, ↓ IgE) | |||||
| Lymphocytes | No effect on T or B cell development from thymus or bone marrow | No effect on T or B cell development from thymus or bone marrow | Thymus: no effect on T cells | Circulating absolute T cell counts: decreased | Circulating absolute T cell counts: normal | Circulating absolute T cell counts: normal |
| Circulating CD4+ T cell subset: decreased | Circulating CD4+ T cell subset: variable | Circulating CD4+ T cell subset: normal | ||||
| No effect on overall composition of mature B and T cell subsets in spleen | No effect on overall composition of mature B and T cell subsets in spleen | Spleen: no effect on T cells; decreased B220+ IgM+ cells | Circulating CD8+ T cell subset: decreased | Circulating CD8+ T cell subset: variable | Circulating CD8+ T cell subset: normal | |
| Memory T cell counts: decreased | Memory T cell counts: variable | Memory T cell counts: normal | ||||
| Bone marrow: increased B220+ CD25+ and B220+ CD43− | Circulating Tfh (CD4+ CXCR5+ CD45RA): low–normal | Reduction in circulating Tfh (defined as CD4+ CXCR5+ CD45RA−) | Reduction in circulating Tfh (CD4+ CXCR5+ CD45RA−) | |||
| T reg cells: normal | T reg cells: normal | T reg cells: normal | ||||
| B cell counts: decreased in childhood; intermittently within reference range in adulthood | B cell counts: normal when diagnosed in childhood; decreased when diagnosed in adulthood | B cell counts: decreased | ||||
| Circulating naive B cells: increased | Circulating naive B cells: high (children); decreased (adults) | Circulating naive B cells: high (children) | ||||
| Circulating switched memory B cell cells: decreased | Circulating switched memory B cell cells: decreased | Circulating switched memory B cell cells: decreased | ||||
| NK cell counts: decreased | ||||||
| Lymphoid organs | ↓ number and size of GC formation | ↓ number and size of GC formation | Absent lymph nodes; abnormal lymphoid architecture in thymus and spleen | |||
| Myeloid cells | Not reported | Not reported | ↓ CD11b+ monocytes in spleen | Progressive neutropenia | Neutropenia (n = 2) | Not reported |
The immunological findings in the mouse (top) and clinical features in humans (bottom) are listed. BCG, Bacillus Calmette-Guérin; RA, rheumatoid arthritis; IBD, inflammatory bowel disease; LGL-T, large granular lymphocyte T cells; SCC, squamous cell carcinoma.