Hyperimmunoglobulinemia syndrome M

Hyper-IgM syndrome (HIGM) is a group of primary immunodeficiencies characterized by normal or elevated serum immunoglobulin M concentrations and a marked decrease or complete absence of immunoglobulins of other classes (G, A, E). Hyper-IgM syndrome is a rare immunodeficiency, with a population frequency of no more than 1 case per 100,000 newborns.

History of the disease

The first descriptions of this syndrome appeared in 1961, F. Rosen et al. published a clinical case of recurrent purulent infections in two brothers, and then P. Burtin gave another case history of a similar male patient. All patients had a low level of IgG against the background of increased IgM. Due to the fact that the patients had a dissociation between normal or increased IgM and decreased or undetectable IgG, this syndrome was designated as "dysgammaglobulinemia".

In 1974, at a meeting of the World Health Organization working group on immunodeficiencies, this disease was named immunodeficiency with high IgM or hyper-IgM syndrome (HIGM). For more than ten years, the nature of the cellular defect in this disease remained unclear. It was assumed that the cause was in B-lymphocytes with an internal defect in switching immunoglobulin isotypes, and the immunodeficiency was classified as humoral. However, the defect in antibody production could not explain the high sensitivity of patients to opportunistic infections, which suggested disturbances in the cellular link of immunity. This was confirmed by the results of studies showing that B-lymphocytes of patients with hyper-IgM syndrome can differentiate into IgG-producing cells when they are co-cultured in vitro with allogeneic T-lymphocytes. Upon contact with T lymphocytes or other cells, stimulation of B lymphocytes via the CD40 receptor can activate proliferation or apoptosis, depending on the stage of B cell differentiation. CD40 expression is widely represented on various cells of the immune system: primarily on B lymphocytes, macrophages, dendritic and some epithelial and endothelial cells, as well as on carcinoma cells. The interaction of CD40 and its ligand (CD40L) is necessary for terminal differentiation of B cells in the terminal centers of lymph nodes and is a key event in the switching of immunoglobulin isotypes. Disruption of various stages of this signaling cascade leads to the clinical and laboratory picture of hyper-IgM syndrome.

It is now known that hyper-IgM syndrome is a heterogeneous condition based on various molecular defects. To date, four molecular genetic defects have been identified that lead to the development of hyper-IgM syndrome. However, patients have been described in whom none of the known genetic defects could be identified. In addition, variants of secondary hyper-IgM syndrome associated with congenital rubella, malignant tumors, and the use of antiepileptic drugs have been described.

According to the current classification, only HIGM1 and HIGM3 are classified as immunodeficiencies with a combined defect of T and B lymphocytes/

Characteristics of hyper-IgM syndrome variants

Disease	Gene	Type of inheritance	Serum immunoglobulins	Cellular immunity
HIGM1	CD40L	HS	IgM is elevated or normal, other levels are reduced	Suffering
NUM2	AID	AR	IgG and IgA are reduced	Intact
HIGM3	CD40	AR	IgM is elevated or normal, the rest are sharply reduced	Suffering
HI6M4	UNG	AR	IgG and IgA are reduced	Intact
HIGM5?	?	Sporadic AR	IgG and IgA are reduced	Intact

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