Patients are at risk for sinopulmonary infections with encapsulated bacterial organisms as well as opportunistic infections (Pneumocystis and Cryptosporidium). CD40 deficiency is a combined B cell and T cell immunodeficiency while AID and UNG deficiency are B cell intrinsic immunodeficiencies.ĬD40 deficiency causes an AR form of HIGM that is clinically identical to CD40 ligand deficiency. A fourth type of AR Hyper IgM (HIGM 4) has been identified but the molecular cause has not been identified. Three types of autosomal recessive Hyper IgM syndromes have been characterized: CD40 deficiency, AID deficiency and UNG deficiency. The molecular cause for these AR HIGM patients remains unknown. It should be noted that one-half of AR HIGM cases caused by B cell intrinsic defects are not caused by AID or UNG deficiency. HSCT is not indicated for AID or UNG deficiency because these are B cell intrinsic defects and patients are not susceptible to opportunistic infections.Ĩ. A single successful HSCT for a patient with CD40 deficiency has been reported by Mazzolari et al.ħ. However, there is limited data regarding the use of HSCT for treatment of this disease. As with CD40L deficiency, HSCT is a consideration for patients with CD40 deficiency. Patients with CD40 deficiency additionally require PJP prophylaxis with trimethoprim-sulfamethoxazole. The mainstay of therapy for all three types of AR HIGM is antibody replacement therapy with IVIG.Ħ. Definitive diagnosis for CD40, AID, and UNG deficiency is made by gene sequencing.ĥ. Flow cytometry for analysis CD40 expression on the surface of B cells can be useful for diagnosis of CD40 deficiency.Ĥ. The switched memory B cell (CD27+IgD-IgM-) population is markedly reduced.ģ. Patients have low IgG and IgA but normal or elevated IgM and poor specific IgG antibody responses. Lymphoid hyperplasia is a common clinical finding. Patients develop recurrent bacterial sinopulmonary infections but do not develop opportunistic infections.
UNG removes uracil residues generated by AID to help create DNA breaks that allow for class-switch recombination. UNG Deficiency (HIGM 5): UNG deficiency causes a B cell intrinsic form of HIGM that does not result in impaired function of T cells, monocytes, or dendritic cells. The switched memory B cell (CD27+IgD-IgM-) population is markedly reduced. Lymphoid hyperplasia and autoimmunity (thrombocytopenia, hemolytic anemia, autoimmune hepatitis) are common clinical findings. Deamination of cytidine to uracil on single-stranded DNA by AID followed by the removal of uracil residues by UNG leads to the introduction of DNA breaks and initiation of class-switch recombination. AID is a protein expressed only in activated B cells. The impaired IL-12/IFN- signaling pathway is likely to be responsible for the phenotype of opportunistic infections.ĪID Deficiency (HIGM 2): AID deficiency causes a B cell intrinsic form of AR HIGM that does not result in impaired function of T cells, monocytes, or dendritic cells. The switched memory B cell population is markedly reduced. As a result, patients have low IgG and IgA but normal or elevated IgM and poor specific IgG antibody responses. The CD40-CD40L interaction is responsible for inducing antibody class-switching (from IgM to IgG, IgA, and IgE) and generating memory B cells. Patients are at risk for sinopulmonary infections with encapsulated bacteria as well as opportunistic infections (Pneumocystis and Cryptosporidium). CD40 deficiency is a combined B cell and T cell immunodeficiency while AID and UNG deficiency are B cell intrinsic immunodeficiencies.ĬD40 Deficiency (HIGM 3): CD40 deficiency causes an AR form of HIGM that is clinically identical to CD40 ligand deficiency. A fourth type of AR HIGM (HIGM 4) has been identified but the molecular cause has not been identified. Three types of autosomal recessive (AR) HIGM syndrome have been identified: CD40 deficiency, AID deficiency, and UNG deficiency. Both X-linked and autosomal recessive forms of disease have been described.Ģ. Hyper IgM syndrome (HIGM) is an antibody deficiency syndrome characterized by impaired class-switch recombination (which allows antibody isotype production to change from IgM to IgG, IgA, or IgE).
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