Immunological methods of diagnosing hereditary diseases

Recently, as the important immunological marker of population genetics, the main complex of histocompatibility - HLA (Human Leukocyte Antigens) began to be considered. Antigens of this system are determined immunologically in blood leukocytes. The complex of HLA genes is compactly located on the short arm of chromosome 6 (6p21.3). Localization of this system and the length of the location of its loci on the chromosome made it possible to calculate that the complex is about 1/1000 of the gene pool of the organism. Histocompatibility antigens are involved in the regulation of the body's immune response, in maintaining immune homeostasis. Due to its polymorphism and compactness of localization of antigens, HLA has acquired great importance as a genetic marker.

Currently, more than 200 alleles of this system are found, it is the most polymorphic and biologically significant of the genetic systems of the human body. Violations of various functions of the main histocompatibility complex contribute to the development of a number of diseases, primarily autoimmune, oncological, and infectious.

In accordance with the arrangement of the HLA complex, the following loci are distinguished in chromosome 6: D / DR, B, C, A. More recently, new loci G, E, H, F have been discovered, their biological role is actively studied at the present time. In the main complex of histocompatibility, three classes of antigens are distinguished. Class I antigens are encoded by loci A, B, C. The new loci also belong to this class. Class II antigens are encoded by the loci DR, DP, DQ, DN, DO. Genes I and II classes encode transplantation antigens. Class III genes encode complement components (C2, C4a, C4b, Bf), as well as the synthesis of isoforms of a number of enzymes (phosphoglucomutase, glycoxylase, pepsinogen-5, 21-hydroxylase).

The presence of a person associated with a certain disease of Ar allows us to assume an increased predisposition to this pathology, and with some correlations, on the contrary, resistance to it.

Determination of antigens of the HLA system is performed on lymphocytes isolated from peripheral blood, using histotyping sera in a microlymphotoxic reaction or by molecular genetic methods.

Establishing associative links between diseases and antigen of the main histocompatibility complex allows:

• identify groups at increased risk of developing the disease;
• to determine its polymorphism, that is, to identify groups of patients with features of the course or pathogenesis of the disease; in the same plan, an analysis of the synthropy of diseases, the elucidation of the genetic preconditions for combining various forms of pathology; association with antigens that determine resistance to diseases, allows to identify persons with a reduced risk of this pathology;
• conduct differential diagnosis of diseases;
• determine the forecast;
• to develop optimal treatment tactics.

Due to the fact that direct communication with the antigens of the main histocompatibility complex is not traced for most diseases, a theory of "two genes" has been proposed to explain the association between diseases and antigens of HLA, according to which the gene (genes) of the immune response (Ir gene) , closely related to HLA antigens and genes regulating the immune response. Protective genes determine resistance to diseases, and genes-provocateurs - sensitivity to certain diseases.

The relative risk of disease for individuals with appropriate genotype is calculated according to the formula: x = [h _p × (1 - h _c )] / [h _c × (1 - h _p )], where h _p - characteristic frequency in patients, and h _c - in the control group.

The relative risk shows the association value of the disease with a certain Ar / Ar of the HLA system (gives an idea of how many times the risk of disease is in the presence of Ar compared with its absence). The more this indicator in the patient, the higher the associative relationship with the disease.

Association of Human Diseases with HLA-Ar (gene frequency,%)

Diseases	HLA	Control group,%	Sick,%	Relative risk
Rheumatology
Ankylosing spondylitis	V27	5-7	90-93	90-150
Wright Syndrome	V27	6-9	69-76	32-49.6
Arthritis caused by infections:
- Yersinia	V27		58-76	17.59
- Salmonella	V27		60-69	17.57
Arthritis psoriatic	B13		9-37	4.79
Rheumatoid arthritis	Dw4	12-19	48-72	3.9-12.0
	DR4	20-32	70	4.9-9.33
Behcet's Syndrome	AT 5	13	48-86	7.4 - 16.4
Hard currency	AT 5		11-34	1.83
	AT 8		19-48	2.11
	Bw15	6-10	21-40	5.1
	DR2	26.4	57.1	3.80
	DR3	22.2	46.4	2.90
Gujero-Sjogren's Syndrome	AT 8		38-58	3.15
	Dw3	26th	69-87	19.0
Cardiology
CHD	AT 7	27.8	45.8	2.19
	B14	7.5	14.8	2.14
	B15	11.1	20.4	2.05
	Сw4	18.7	32.8	2.12
Hypertonic disease	B18	10.4	22.6	2.52
	Аw19	12.6	28.3	2.74
Endocrinology
Type 1 diabetes mellitus	AT 8	32	52-55	2.1-2.5
	B18		5-59	1.65
	B15	12	18-36	1.89-3.9
	Dw3	26th	48-50	2.9-3.8
	Dw4	19	42-49	3.5-3.9
	DR3 DR3 / DR4	20	60	6.10 33
Hyperthyroidism	AT 8	21	35-49	2.34-3.5
	D3	26th	61	4.4
	DR3	20	51	4.16
Subacute thyroiditis (de Kervena)	Bw35	13	63-73	16.81
	Dw1		33	2.1
Addison's disease	AT 8		20-80	3.88-6.4
	Dw3	26th	70-76	8.8-10.5
Isenko-Cushing syndrome	A1		49	2.45
Gastroenterology
Pernicious anemia	AT 7	19	26-52	1.7-3.1
	DR5	6th	25	5.20
Atrophic gastritis	AT 7		37	2.55
Peptic ulcer disease of the duodenum	A2	48.1	61.3	1.7
	A10	20.6	63.3	6.65
	B14	4.0	10.3	2.76
	B15	6.6	24.4	4.56
	B40	9.72	23.3	2.82
Autoimmune Hepatitis	AT 8	16	37-68	2.8-4.1
	DR4	24	71	7.75
Carriers of HBsAg	Bw41		12	11.16
	B15		10-19	0.29

Diseases	HLA	Control group,%	Sick,%	Relative risk
Dermatology
Psoriasis	Bw17	6-8	22-36	3.8-6.4
	B13	3-5	15-27	4.2-5.3
	Bw16	5	15	2.9
Herpetiform dermatitis	AT 8	27-29	62-63	4.00-4.6
	DR3	19	80	16.60
Scleroderma	AT 7	24	35	1.7
Pemphigus	A10			3.1
Atopic dermatitis	B13	6.86	21.28	3.67
	V27	9.94	25.53	3.11
	A10 / B13	0.88	8.51	10.48
Eczema	A10	19.64	36.67	2.37
	V27	9.94	26.67	3.29
Urticaria and edema Quincke	B13	6.86	21.21	3.65
	B5.8	1.42	12.12	9.57
	B5.35	0.71	6.06	9.02
Neurology
Multiple sclerosis	A3	25	36-37	2.7-2.8
	AT 7	25-33	36-42	1.4-2.0
	Dw2	16-26	60-70	4.3-12.2
	DR2	35	51.2	1.95
	DR3	20	32.5	1.93
Myasthenia gravis	AT 8	21-24	52-57	3.4-5.0
	A1	20-25	23-56	3.8
	DR3	26th	50	2.5
Pulmonology
Bronchial asthma (who fell ill at the age of 19-30 years)	AT 21	4.62	12.5	2.95
	B22	9.94	19.64	2.22
	V27	12.31	37.5	4.27
	B35	0.11	5.36	51.4
	В27 / 35	0.47	7.14	16.2
Other diseases
Vasomotor rhinitis	A3	26.98	52.38	2.98
	B17	7.57	28.57	4.88
	A3 / 10	2.72	23.83	11.18
	B7 / 17	0.47	9.52	22.28

The data in the table show that the strongest associative links are identified for diseases with a polygenic or multifactorial type of inheritance.

Thus, the determination of antigens of the main histocompatibility complex on blood cells (leukocytes) allows to determine the degree of individual predisposition to a certain disease, and in some cases to use the results of studies for differential diagnosis, evaluation of the forecast and choice of treatment tactics. For example, the detection of antigens HLA-B27 is used in the differential diagnosis of autoimmune diseases. It is found in 90-93% of patients of the Caucasoid race with ankylosing spondylitis and Reiter's syndrome. In healthy members of this race, HLA-B27 antigens are detected in only 5-7% of cases. HLA-B27 antigens are often found in psoriatic arthritis, chronic inflammatory bowel diseases that occur with sacroiliitis and spondylitis, uveitis and reactive arthritis.

[1], [2], [3], [4], [5], [6], [7]