Hyperimmunoglobulinemia syndrome M

Hyper-IgM syndrome (HIGM) is a group of primary immunodeficiencies characterized by a normal or elevated concentration of serum immunoglobulin M, and a marked decrease or absence of immunoglobulins of other classes (G, A, E). Hyper-IgM syndrome refers to rare immunodeficiencies, the frequency in the population does not exceed 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 cited another medical history of a similar male patient. All patients had a low IgG level against a background of increased IgM. In view of the fact that patients had a dissociation between normal or elevated IgM and reduced or undetectable IgG, this syndrome was designated as "disgammaglobulinemia".

In 1974, at a meeting of the working group of the World Health Organization on immunodeficiency, this disease was called immunodeficiency with high IgM or hyper-IgM syndrome (HIGM). For more than ten years, the nature of the cellular defect in this disease has remained unclear. It was assumed that the cause is B-lymphocytes having an internal defect in switching isotypes of immunoglobulins, and immunodeficiency was classified as humoral. However, the defect in antibody production could not explain the high sensitivity of patients to opportunistic infections, which suggested violations in the cell link of immunity. This was confirmed by the results of studies that showed that B-lymphocytes of patients with hyper-IgM syndrome can be differentiated by IgG-producing cells, when they are cultured in vitro from allogeneic T-lymphocytes. Upon contact with T lymphocytes or other cells, stimulation of the B lymphocyte through the CD40 receptor can activate proliferation or apoptosis, depending on the stage of B cell differentiation. Expression of CD40 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 the lymph nodes and is a key event in the switching of immunoglobulin isotypes. Violation of the various stages of this signaling cascade leads to a clinical and laboratory picture of hyper-IgM syndrome.

It is now known that the hyper-IgM syndrome is a heterogeneous state, which is based on various molecular defects. To date, four molecular-genetic defects have been identified, leading to the development of hyper-IgM syndrome. However, patients who have failed to detect any of the known genetic defects are described. In addition, variants of secondary hyper-IgM syndrome associated with congenital rubella, malignant tumors and the use of antiepileptic drugs are described.

According to modern classification, only HIGM1 and HIGM3 refer to immunodeficiency with a combined defect of T and B lymphocytes /

Characteristics of variants of hyper-IgM syndrome

Disease	Gene	Inheritance type	Serum Immunoglobulins	Cep body immunity
HIGM1	CD40L	HS	IgM elevated or normal, other cuts reduced	Suffers
NUMM2	AID	AR	IgG and IgA are reduced	Intact
HIGM3	CD40	AR	IgM elevated or normal, others drastically reduced	Suffers
HI6M4	UNG	AR	IgG and IgA are reduced	Intact
HIGM5?	?	Sporadically AR	IgG and IgA are reduced	Intact

[1], [2], [3], [4], [5], [6]