TABLE 3.
Genetic, immunological and clinical features in monogenic forms of PID in the clinical spectrum of CVID with liver involvement.
| Genetic defect (OMIM) | Effect on protein | Inheritance | Most frequent clinical manifestations | Most frequent Immune phenotype | Liver involvement |
| ICOS (86–91) (604558) | LOF | AR | Respiratory tract infections Skin infections Opportunistic infections Autoimmunity (i.e., cytopenias and arthritis) |
Pan-hypogammaglobulinemia Low/absent naïve B-cells and switched-memory B cells Low TFH cells Low CTLA-4 Low production of Th1/Th2/Th17 cytokines |
HHV-6 hepatitis Non-infectious hepatitis (drug-induced?) Hepatomegaly |
| NFKB1 (92–98) (164011) | LOF (H) | AD | Respiratory tract infections Lymphadenopathy Splenomegaly, GLILD Autoimmune cytopenias Hematological malignancy |
Pan-hypogammaglobulinemia Low/absent switched-memory B cells and plasmablasts Normal T-cell phenotype |
Increase of liver enzymes Fibrosis and cirrhosis with Liver insufficiency |
| NFKB2 (99, 100) (164012) | LOF (H) | AD | Respiratory tract infections, Skin infections, Opportunistic infections Lymphocytic organ infiltration Autoimmunity ACTH-deficiency + other endocrinological abnormalities |
Pan-hypogammaglobulinemia Low marginal zone and switched-memory B cells Expansion of CD4+ T cell with low naïve T cells Low Treg, TFH and TH17 cells |
Increase of liver enzymes Lymphocytic infiltration Steatosis Autoimmune hepatitis |
| CTLA-4 (101–105) (123890) | LOF (H) | AD | Lymphoproliferation, Respiratory tract infections and bronchiectasis Enteropathy Autoimmune cytopenias, Atopic dermatitis Endocrinopathy Neurological disroders EBV-driven lymphomas |
Pan-hypogammaglobulinemia Low CD4+ T cells with normal Treg cells Low switched-memory B cells Increase of CD21low B cells |
Unspecified liver involvement in 12% patients |
| LRBA (106–110) (606453) | LOF | AR | Autoimmunity cytopenias Enteropathy GLILD Lymphproliferation and lymphocytic infiltration of organs Respiratory and gastrointestinal infections Type 1 Diabetes |
Pan-hypogammaglobulinemia Low switched memory B cells and plasmablasts Normal or increased double negative T cells Normal or low Treg cells |
Hepatomegaly Autoimmune hepatatis Peri-portal and perisinusoidal fibrosis Granulomata |
| PI3Kδ pathway (111–118) (602839; 171833; 601728) | GOF of PI3Kδ (APDS1) LOF of PI3Kδ (APDS2) LOF of PTEN (APDS3) |
AD | Respiratory tract infections and bronchiectasis Opportunistic and viral infections Lymphoproliferation Autoimmune cytopenia Enteropathy Neurodevelopmental delay |
Low IgG and IgA Low naïve and switched-memory B cells Increase of transitional and CD21low B cells Low CD4+ naïve T-cells Impaired T-cell response to IL-2 |
Increase of liver enzymes NRH Sclerosing cholangitis Cirrhosis Cryptosporidium infection |
| ADA2 (119–122) (607575) | LOF | AR | Recurrent infections Lymphoproliferation Polyarteritis nodosa Livedo reticularis Ischemic/hemorrhagic stroke Bone marrow aplasia Neurological impairment |
Hypogammaglobulinemia Low switched-memory B cells Impaired B cell response to CD40-L and IL-21 |
Increase of liver enzymes NRH with portal sclerosis Vasculitis Hepatomegaly |
| IL-21R (123–127) (605383) | LOF | AR | Respiratory tract infections and bronchiectasis Opportunistic infections Lymphoproliferation Inflammatory skin disease |
Hypogammaglobulinemia Impaired B cell response to IL-21 Variable T cell response to mitogens |
Cryptosporidium infection |