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Immunologic methods of diagnostics of hereditary diseases
Last reviewed: 06.07.2025

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Recently, the main histocompatibility complex - HLA (Human Leukocyte Antigens) has come to be considered as an important immunological marker of population genetics. The antigens of this system are determined immunologically in blood leukocytes. The HLA gene complex is compactly located on the short arm of chromosome 6 (6p21.3). The localization of this system and the extent of its loci on the chromosome allowed us to calculate that the complex constitutes approximately 1/1000 of the gene pool of the organism. Histocompatibility antigens participate in the regulation of the immune response of the organism, in maintaining immune homeostasis. Due to their polymorphism and compact localization of HLA antigens, they have acquired great importance as a genetic marker.
Currently, more than 200 alleles of this system have been discovered; it is the most polymorphic and biologically significant of the human body's genetic systems. Disorders of various functions of the major histocompatibility complex contribute to the development of a number of diseases, primarily autoimmune, oncological, and infectious.
According to the location of the HLA complex on chromosome 6, the following loci are distinguished: D/DR, B, C, A. New loci G, E, H, F have been discovered relatively recently; their biological role is currently being actively studied. Three classes of antigens are distinguished in the major histocompatibility complex. Class I antigens are encoded by loci A, B, C. New loci also belong to this class. Class II antigens are encoded by loci DR, DP, DQ, DN, DO. Genes of classes I and II encode transplantation antigens. Genes of class III 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 Ag associated with a certain disease in a person allows us to assume an increased predisposition to this pathology, and in some correlations, on the contrary, resistance to it.
Determination of HLA system antigens is carried out on lymphocytes isolated from peripheral blood using histotyping sera in a microlymphocytotoxic reaction or molecular genetic methods.
Establishing associative links between diseases and the antigen of the major histocompatibility complex allows:
- identify groups at increased risk of developing the disease;
- determine its polymorphism, that is, identify groups of patients with features of the course or pathogenesis of the disease; in this regard, an analysis of the syntropy of diseases can be carried out, identifying the genetic prerequisites for the combination of various forms of pathology; association with antigens that determine resistance to diseases allows identifying individuals with a reduced risk of developing this pathology;
- conduct differential diagnostics of diseases;
- determine the prognosis;
- develop optimal treatment tactics.
Since most diseases do not have a direct connection with the antigens of the major histocompatibility complex, the "two-gene" theory was proposed to explain the association between diseases and HLA antigens. According to this theory, there is an immune response gene (genes) (Ir gene) that is closely associated with HLA antigens and genes that regulate the immune response. Protector genes determine resistance to diseases, and provocative genes determine sensitivity to certain diseases.
The relative risk of the disease for individuals with the corresponding genotype is calculated using the formula: x = [h p × (1 - h c )] / [h c × (1 - h p )], where h p is the frequency of the trait in patients, and h c is the frequency in individuals in the control group.
Relative risk shows the magnitude of the association of the disease with a certain Ag/Ag of the HLA system (gives an idea of how many times higher the risk of developing the disease is in the presence of Ag compared to its absence). The higher this indicator in a patient, the higher the associative connection with the disease.
Association of human diseases with HLA-Ag (gene frequency,%)
Diseases |
HLA |
Control group,% |
Sick,% |
Relative risk |
Rheumatology |
||||
Ankylosing spondylitis |
B27 |
5-7 |
90-93 |
90-150 |
Reiter's syndrome |
B27 |
6-9 |
69-76 |
32-49.6 |
Arthritis caused by infections: |
||||
- Yersinia |
B27 |
58-76 |
17.59 |
|
- Salmonella |
B27 |
60-69 |
17.57 |
|
Psoriatic arthritis |
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 |
B5 |
13 |
48-86 |
7.4-16.4 |
SKV |
B5 |
11-34 |
1.83 |
|
B8 |
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 |
|
Gougerot-Sjogren syndrome |
B8 |
38-58 |
3.15 |
|
Dw3 |
26 |
69-87 |
19.0 |
|
Cardiology |
||||
IHD |
B7 |
27.8 |
45.8 |
2.19 |
B14 |
7.5 |
14.8 |
2.14 |
|
B15 |
11.1 |
20.4 |
2.05 |
|
Cw4 |
18.7 |
32.8 |
2.12 |
|
Hypertension |
B18 |
10.4 |
22.6 |
2.52 |
Aw19 |
12.6 |
28.3 |
2.74 |
|
Endocrinology |
||||
Type 1 diabetes |
B8 |
32 |
52-55 |
2.1-2.5 |
B18 |
5-59 |
1.65 |
||
B15 |
12 |
18-36 |
1.89-3.9 |
|
Dw3 |
26 |
48-50 |
2.9-3.8 |
|
Dw4 |
19 |
42-49 |
3.5-3.9 |
|
DR3 DR3/DR4 |
20 |
60 |
6.10 33 |
|
Hyperthyroidism |
B8 |
21 |
35-49 |
2.34-3.5 |
D3 |
26 |
61 |
4.4 |
|
DR3 |
20 |
51 |
4.16 |
|
Subacute thyroiditis (de Quervain's) |
Bw35 |
13 |
63-73 |
16.81 |
Dw1 |
33 |
2.1 |
||
Addison's disease |
B8 |
20-80 |
3.88-6.4 |
|
Dw3 |
26 |
70-76 |
8.8-10.5 |
|
Itsenko-Cushing syndrome |
A1 |
49 |
2.45 |
|
Gastroenterology |
||||
Pernicious anemia |
B7 |
19 |
26-52 |
1.7-3.1 |
DR5 |
6 |
25 |
5.20 |
|
Atrophic gastritis |
B7 |
37 |
2.55 |
|
Peptic ulcer 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 |
B8 |
16 |
37-68 |
2.8-4.1 |
DR4 |
24 |
71 |
7.75 |
|
HBsAg carriers | 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 |
|
Dermatitis herpetiformis |
B8 |
27-29 |
62-63 |
4.00-4.6 |
DR3 |
19 |
80 |
16.60 |
|
Scleroderma |
B7 |
24 |
35 |
1.7 |
Pemphigus |
A10 |
3.1 |
||
Atopic dermatitis |
B13 |
6.86 |
21.28 |
3.67 |
B27 |
9.94 |
25.53 |
3.11 |
|
A10/B13 |
0.88 |
8.51 |
10.48 |
|
Eczema |
A10 |
19.64 |
36.67 |
2.37 |
B27 |
9.94 |
26.67 |
3.29 |
|
Urticaria and Quincke's edema |
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 |
B7 |
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 |
B8 |
21-24 |
52-57 |
3.4-5.0 |
A1 |
20-25 |
23-56 |
3.8 |
|
DR3 |
26 |
50 |
2.5 |
|
Pulmonology |
||||
Bronchial asthma (in patients aged 19-30 years) |
B21 |
4.62 |
12.5 |
2.95 |
B22 |
9.94 |
19.64 |
2.22 |
|
B27 |
12.31 |
37.5 |
4.27 |
|
B35 |
0.11 |
5.36 |
51.4 |
|
B27/35 |
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 presented in the table show that the strongest associative links are found for diseases with a polygenic or multifactorial type of inheritance.
Thus, the determination of antigens of the major histocompatibility complex on blood cells (leukocytes) allows us to identify the degree of individual predisposition of a person to a certain disease, and in some cases use the research results for differential diagnostics, prognosis assessment and selection of treatment tactics. For example, the detection of HLA-B27 antigens is used in the differential diagnostics of autoimmune diseases. It is detected in 90-93% of patients of the Caucasian race with ankylosing spondylitis and Reiter's syndrome. In healthy representatives of this race, HLA-B27 antigens are detected in only 5-7% of cases. HLA-B27 antigens are often detected in psoriatic arthritis, chronic inflammatory bowel diseases occurring with sacroiliitis and spondylitis, uveitis and reactive arthritis.