Ultrasonic lymphoid hyperplasia of the intestine: causes, symptoms, diagnosis, treatment

Benign nodular lymphoid hyperplasia of the small intestine with a common variable immunodeficiency

In the problem of the pathology of the small intestine, immunodeficiency states, accompanied by the development of one of the varieties of lymphoproliferative processes, benign nodular lymphoid hyperplasia, are of particular interest.

The small intestine, having an extensive border surface, is in constant contact with numerous antigens: alimentary, viral, medicinal, pathogenic and opportunistic (conditionally pathogenic) intestinal flora.

In connection with close contact with antigens in the mucosa of the small intestine, a powerful lymphoid tissue develops, forming an immunocompetent system in which cell-type reactions occur, as well as sensitization of lymphocytes with subsequent differentiation into plasma cells synthesizing immunoglobulins.

Lymphoid structures of the small intestine are part of a single MALT-system (MALT-mucosal associated lymphoid tissue), a lymphoid tissue associated with the mucous membranes that forms a special secretory system in which cells that synthesize immunoglobulins circulate.

The lymphoid tissue of the small intestine wall is represented by the following structures located at different anatomic levels: intraepithelial lymphocytes localized between enterocytes of villous epithelium and mucosal crypts; lymphocytes, which are part of its own plate; group lymphoid follicles of the submucosa and solitary follicles.

Causes of development and pathogenesis of nodular lymphoid hyperplasia of the intestine

The source of intraepithelial lymphocytes are the lymphocytes of the propria of the mucous membrane, which can migrate through the basal membrane of the integument epithelium in both directions and sometimes go into the lumen of the gut. Intraepithelial lymphocytes normally constitute about 20% of all cells of the small intestinal mucosa epithelium. On average 100 enterocytes in the jejunum account for 20 intraepithelial lymphocytes, in the iliac - 13 lymphocytes. P. Van den Brande et al. (1988) in the study of material taken from the ileum in control preparations found that mainly intraepithelial lymphocytes are T-lymphocytes (T-suppressors), rarely B-forms. According to data provided by L. Jaeger (1990), intraepithelial lymphocytes are represented by T cells, of which 80-90% of T-suppressor cells, single cells had an NK-cell marker, B-lymphocytes were absent. However, there is another point of view: intraepithelial lymphocytes belong to a special subtype of lymphocytes.

Intraepithelial lymphocytes have immunoregulatory activity, affecting the synthesis of immunoglobulins in the B cells of the stroma of the propria of the mucosa. Their cytotoxic potential is relatively low.

The number of lymphocytes diffusely located in the stroma of the own plate of the small intestine mucosa in a healthy person is 500-1100 cells per 1 mm ^{2 of} area. They include B- and T-lymphocytes, as well as "zero" cells. Among the B lymphocytes, IgA-synthesizing cells predominate. In the normal mucosa of the intestine, about 80% of the plasma cells synthesize IgA, 16% - IgM, about 5% - IgG. T-lymphocytes are represented mainly by T-helpers and T-suppressors with predominance of T-helpers in the unmodified mucosa.

A special structure is possessed by group lymphoid follicles (Peyer's plaques) located in the submucosa base throughout the mucous membrane of the small intestine, but especially well developed in the ileum.

Above the group lymphoid follicles is a "vault" - a section of the mucous membrane of a hemispherical shape, in which there are no villi and the number of goblet cells is sharply reduced. The structural feature of the epithelium covering the "arch" is the presence of specialized M-cells, on the apical surface of which there are no microvilli, glycocalyx, and in the cytoplasm - terminal network and lysosomes. It is characteristic to develop microfoldings instead of microvilli, which are based on peculiar outgrowths and convolutions. M cells are in close spatial association with intraepithelial lymphocytes, which are contained in large folds of the cytolemma or its pockets coming from the basal surface of the M cells. There is a close contact between the M-cells and a number of located kamechatye enterocytes, as well as with macrophages and lymphocytes of the propria of the mucous membrane. M-cells are capable of pronounced pinocytosis and participate in the transport of macromolecules from the intestine to Peyer's plaques. The main function of M-cells is the reception and transport of the antigen, that is, they play the role of specialized cells that assure the absorption of antigens.

The germinal center of follicles of Peyer's plaques, according to P. Van den Brande et al. (1988), normally contains large and small B-lymphocytes and a small number of T-helpers and T-suppressors. The mantle zone includes IgM-producing B-lymphocytes and a ring formed by T-lymphocytes, in which T-helpers are significantly larger than T-suppressors. Lymphocytes of Peyer's plaques do not possess the properties of killers. There is also evidence that B cells of Peyer's plaques are unable to form antibodies. This feature may be due to a low content of macrophages in their germinative centers. However, Peyer's plaque lymphocytes are important precursors for Ig-producing cells of the lamina propria of the small intestinal mucosa.

Through specialized epithelial M-cells, antigens penetrate into Peyer's plaques and stimulate antigen-reactive lymphocytes. After activation, lymphocytes with lymphoma pass through the mesenteric lymph nodes, enter the blood and own plate of the small intestine mucosa, where they are converted into effector cells producing immunoglobulins, mainly IgA and protecting vast areas of the intestine, synthesizing antibodies. Similar cells migrate to other organs. In Peyer's plaques, 55% of all cell elements in their structure are B-lymphocytes, 30% in peripheral blood, 40% in the spleen, 40% in the red bone marrow, 25% in the lymph nodes, thymus gland - only 0.2%. Such a high content of B-lymphocytes in the group lymphoid follicles attests to the predominant role of Peyer's plaques in the production of B-lymphocytes.

The solitary lymphoid follicles of the small intestine mucosa do not have a close connection with the epithelium. They include B-lymphocytes, T-lymphocytes and macrophages. So far, the features of the function have not been studied enough.

Of great importance in the system of immune mechanisms is also the state of local immunity in the mucous membranes of the body, in particular the small intestine.

Infection of the mucous membranes with viruses and bacteria begins with their adhesion to the epithelial cells of the integument epithelium. The function of protection in external secrets is performed mainly by secretory IgA (SIgA). Being associated with bacteria and viruses, SIgA prevents their adhesion to the surface of the epithelium and provides the "first line of defense" of the mucous membranes from the influence of antigens.

SIgA is found in the secrets of all the exocrine glands: milk, saliva, gastrointestinal secrets, secrets of the mucous membranes of the respiratory tract (nasal, pharyngeal, tracheobronchial), in tear fluid, sweat, secrets of the genitourinary system.

Secretory IgA is a complex complex consisting of a dimer, a molecule of a secretory component protecting SIgA from proteolysis, and a J chain molecule. The J-chain (joing-connecting) is a cysteine-enriched polypeptide with a molecular weight of 15,000. The J-chain is synthesized, like IgA, predominantly by the plasmatic cells of the lamina propria of the small intestinal mucosa. The secretory component (secretory piece) is a glycoprotein and consists of one polypeptide chain with a molecular weight of 60,000 and is synthesized locally by epithelial cells.

Thus, the lymphoid tissue of the small intestine plays the role of an active barrier when introducing foreign antigens. In a healthy person, her work is harmonious and fully protects the body from the effects of pathogenic factors. However, in pathology, in particular in the development of a general variable immunodeficiency with a predominance of a lack of antibody production, in response to intense antigenic stimulation in the mucosa of the small intestine and in some cases in the antrum part of the stomach and colon, an additional structure develops - benign nodular lymphoid hyperplasia, correlation in the synthesis of immunoglobulins due to the release of a large number of lymphocytes into the stroma of the propria of the mucous membrane.

According to the histological classification of intestinal tumors of the WHO, adopted in Geneva in 1981, nodular lymphoid hyperplasia is classified as benign tumor-like lesions, which look like multiple polypoid formations in the small intestine mucosa, based on reactively hyperplastic lymphoid tissue (Geneva, 1981).

For the first time in 1958, V. G. Fircin and S. R. Blackborn discovered numerous nodules on the mucosa of the small intestine, the basis of which was lymphoid tissue.

For benign nodular lymphoid hyperplasia, a clear endoscopic picture, clear radiographic signs, definite morphological criteria and the features of the clinic of the disease are characteristic.

More recently, the researchers drew attention to the relationship of the development of benign nodular lymphoid hyperplasia with a common variable immunodeficiency.

According to P. Hermans et al., The incidence of benign nodular lymphoid hyperplasia in patients with total variable immunodeficiency is 17-70%.

Macroscopically benign nodular lymphoid hyperplasia has the appearance of multiple polypoid structures that do not have a pedicle, 0.2 to 0.5 cm in diameter, protruding above the surface of the small intestinal mucosa.

Benign nodular lymphoid hyperplasia, as a rule, is an endoscopic finding, revealed in the form of nodules against the background of the hyperemic mucosa of the small intestine.

To determine the degree of development and prevalence of this process in the small intestine, the use of probe enterography is successfully used in the diagnosis of benign nodal lymphoid hyperplasia, one of the types of X-ray studies.

In recent years, in our country and abroad, much attention is paid to the study of immunodeficient conditions, in which both isolated defects of cellular and humoral immunity units are observed, and their combination.

In the pathology of the digestive organs, in particular the small intestine, variable immunodeficiency is of great importance with violation of humoral and cellular immunity. The term "variable immunodeficiency with predominance of immunoglobulin deficiency" was proposed by WHO in 1978

At present a number of authors also use the terms "general variable acquired hypogammaglobulinemia with late onset".

In August 1985, at a special meeting of WHO devoted to primary immunodeficiency, a classification was proposed, according to which the following 5 main forms of primary immunodeficiency states are distinguished (WHO classification, 1985):

• immunodeficiency with the predominance of an antibody defect;
• combined immunodeficiency;
• immunodeficiency caused by other major defects;
• deficiency of complement;
• defects of phagocyte function.

Common variable immunodeficiency (common variabeliti immunodeficiency) refers to combined immunodeficiency and subdivided into a general variable immunodeficiency with a predominance of insufficiency of cellular immunity and with a predominance of antibody deficiency.

The general variable immunodeficiency with predominance of antibody deficiency, accompanied by the development of benign knot lymphoid hyperplasia of the small intestine, is a big clinical problem, since on the one hand, nodular lymphoid hyperplasia, being a reactive formation, to some extent contributes to compensating for the lack of synthesis of antibodies in the conditions of the developed immunodeficiency, especially in its early stages, and on the other - it can itself become a source of development of malignant neoplasms - gastrointestinal lymphoma th path.

Clinic of benign nodular lymphoid hyperplasia of the small intestine in patients with a common variable immunodeficiency with a predominance of antibody deficiency includes all the symptoms of the syndrome of this immunological failure and the signs inherent in nodular lymphoid hyperplasia.

Patients note pain in the abdomen, mainly around the navel. With a significant increase in the number of lymphoid nodules, the pain becomes paroxysmal, and because of periodic invagination, intestinal obstruction can occur. In addition, food intolerance, bloating, diarrhea, and weight loss are characteristic.

The average age of patients is 39.36 + 15.28 years, the average duration of the disease is 7.43 ± 6.97 years, weight loss is 7.33 ± 3.8 kg. A relationship between the development of nodular lymphoid hyperplasia and giardiasis has been established. This contingent of patients has an increased risk of developing malignant tumors.

During the exacerbation of the disease, patients noted increased fatigue, general weakness, decrease or total loss of ability to work.

One of the permanent signs of immune deficiency in this pathology is a decrease in the resistance of the body to infections. The so-called contact surfaces serve as the "gateway" of the infection: the intestinal mucosa, the airways, the skin. In the syndrome of antibody deficiency, bacterial infections caused by staphylococci, pneumococci, streptococci, and Haemophilus influenzae predominate.

Characterized by recurrent chronic respiratory diseases: repeated pneumonia, repeated tracheobronchitis, as well as sinusitis, otitis, cystitis, chronic pyelonephritis, furunculosis. With the long course of the disease, emphysema of the lungs, pneumosclerosis can develop. One of the main symptoms is the emergence of splenomegaly.

The results of recent studies suggest that immunodeficiencies are associated with autoimmune diseases such as hemolytic and pernicious anemia, autoimmune neutropenia, thrombocytopenic purpura. Also affects the connective tissue: dermatomyositis, scleroderma, rheumatoid arthritis can develop. With the syndrome of antibody deficiency, sensitivity to encephalitis viruses, meningitis is high.

The most common variable immunodeficiency is accompanied by a syndrome of impaired absorption of varying severity (in 35-95% of cases), often - II and III severity. The development of the syndrome of impaired absorption of the third degree of severity is accompanied by a large loss of body weight, hypoproteinemic edema, anemia, hypocalcemic tetany, osteomalacia, hypercatabolic exudative enteropathy, decreased absorption of vitamin B12 and electrolytes.

Diagnosis of nodular lymphoid hyperplasia of the intestine

One of the main symptoms of the disease is a decrease in serum levels of all three classes of immunoglobulins (AM, G), especially significant in class A, which performs the main barrier function in protecting the mucous membrane from penetration of foreign antigens into the internal environment of the body. With this form of immunodeficiency with nodal lymphoid hyperplasia, a significant fluctuation of the content of various immunoglobulins revealed by radial immunodiffusion in Mancini was observed in a number of patients. However, the use of nonparametric criteria in mathematical processing, in particular Kruskall-Wallace, made it possible to reveal a general pattern in the change in these parameters: a decrease in the IgA level to 36.16% of the control, taken as 100% (p = 0.001), a decrease in IgM to 90, 54% (p = 0.002) and IgG to 87.59% (p = 0.001) of the reference values taken as 100%.

In the mathematical treatment of laboratory data, 44 patients with nodular lymphoid hyperplasia and general variable immunodeficiency were found to have an increase in peripheral blood lymphocyte count to 110.11% (p = 0.002), compared to a control taken as 100%.

However, the results of the study by P. Van den Brande et al. (1988) showed that with nodular lymphoid hyperplasia of the small intestine and general variable immunodeficiency, peripheral blood cells can not produce IgG in vitro in response to mitogen stimulation. In 2 out of 5 examined patients with this pathology, IgM production was induced in vitro, which indicates an incomplete block in the differentiation of B cells.

Immunological examination of patients with benign nodular lymphoid hyperplasia reduced the total number of T-lymphocytes in the peripheral blood by reducing the content of T-helpers. An increase in the number of T suppressors was observed, which could lead to an imbalance in the proportion of CD4 / CD8.

The study of the protein blood spectrum showed that for nodular lymphoid hyperplasia and general variable immunodeficiency, a statistically significant increase in the content of a-globulins to 141.57% (p = 0.001), beta-globulin to 125.99% (p = 0.001) with control values taken as 100%. Mathematical processing allowed to reveal a statistically significant decrease in the content in the blood of α-globulins, γ-globulins, bilirubin and cholesterol. The sugar curve was characterized by a more reduced increase in sugar in the blood after a load characteristic of the syndrome of impaired absorption, compared with the norm.

The structural-functional unit of benign nodular lymphoid hyperplasia is the lymphoid follicle, in which production is balanced, immigration, emigration of cells and their death

With a general variable immunodeficiency, lymphoid nodules can be localized in the mucosa of one, two or all three sections of the small intestine. Sometimes the antral part of the stomach and the large intestine are involved in the process.

Lymphoid follicles are located directly under the cover epithelium, near the basal membrane, or in the superficial layers of the lamina propria of the small intestine mucosa. From the mantle zone of the follicles towards the cover epithelium, migration of lymphocytes in the form of lymphoid pathways is observed. B-lymphocytes are concentrated in the lamina propria zone located between the epithelium and the follicles, as well as T-lymphocytes of the two subtypes: T-helpers and T-suppressors, of which T suppressors predominate in the general variable immunodeficiency.

In the area of the location of lymphoid follicles, the villi of the small intestine are often absent, the surface of the mucous membrane is smoothed.

In these areas, there was a significant increase in the height of kemchatic enterocytes, reaching 52.5 ± 5.0 mkt. Goblet cells are single. However, there was no specialization of enterocytes in the locations of lymphoid follicles. There was a significant increase in the number of intraepithelial lymphocytes represented by T suppressors.

The results of the study of light-optical preparations obtained from a biopsy specimen taken from various parts of the small intestine showed that with nodular lymphoid hyperplasia and general variable immunodeficiency, thinning of the brush border of enterocytes, a reduction in the content of neutral glycosaminoglycans in it, and also dystrophic changes in the cytoplasm were observed. In the stroma of the propria of the mucous membrane against the background of an increased content of small lymphocytes and eosinophils, a decrease in the number of plasma and lymphoplasmacytoid cells is observed, especially when the total variable immunodeficiency is severe.

With simultaneous electron microscopic examination of the biopsy specimens of the mucous membrane of the duodenum, jejunum and ileum, the same type of changes in the kemicite enterocytes of the villi were observed. On the apical surface of a number of enterocytes, the shortening and rarefaction of microvilli, their irregular location, and the development of the syndrome of impaired suction of the third degree - local disappearance. Glycocalix on the surface of microvilli was found in a small amount, and in places it was completely absent. In the cytoplasm of many enterocytes, signs of disorganization have been revealed with varying degrees of severity: the expansion of the tubules of the granular and agranular cytoplasmic network, the swelling of mitochondria with a decrease in the number of cristae in their matrix and the formation of myelin-like structures, and hypertrophy of the lamellar complex.

Lymphoid follicles are formed by germinal centers (follicular, light centers) and mantle zones. The centers were often expanded. Their composition, according to the classification of K. Lennert (1978), includes the following cellular elements: immunoblasts, centroblasts, centrocytes, small lymphocytes, macrophages, stromal cells. The mantle zone is formed by centroblasts, small lymphocytes, plasma cells and stromal cell elements. When studying the cellular composition of lymphoid follicles with monoclonal antibodies for benign nodular lymphoid hyperplasia and general variable immunodeficiency, it was found that they consist mainly of B lymphocytes that do not differentiate into Ig-producing cells and a small number of T cells, among which most of all T-suppressors. Around the follicles also prevailed T-suppressors.

However, AD W. Webster (1987) found IgM in the effinal juice, and in the lamina propria of the small intestine mucosa-IgM-containing cells, there was also a decrease in the luminescence intensity of plasma cells containing IgA, IgM and IgG in patients with total variable immunodeficiency with lymphoid nodosa hyperplasia, which indicates an incomplete block in the differentiation of B-lymphocytes. It is reasonable to assume that in the area around the follicles, the maturation of B-lymphocytes to plasma cells capable of producing immunoglobulins is suppressed by T suppressors.

Results of morphometry of cellular elements of follicles of benign knotted lymphoid hyperplasia with the use of the method of calibrated squares with subsequent mathematical processing made it possible to reveal the cyclicity of the changes in germinal centers and mantle zones, including the six main phases of development. The following phases are distinguished in the germinal zones:

• Phase I is the predominance of centroblasts. In the first phase, centroblasts account for 80% of all cellular elements of the center, centrocytes -3.03%, macrophages - 5.00%.
• II phase - a decrease in the content of centroblasts and an increase in the number of centrocytes. In the II phase, the number of centroblasts decreases to 59.96%, the centrocytes increases to 22.00%, small lymphocytes - up to 7.09%.
• III phase - the same content of centrocytes and centroblasts. In the III phase, the number of centroblasts is 39.99%, centrocytes - 40.0%, small lymphocytes - 9.93%, macrophages - 3.53%.
• IV phase - a decrease in the content of centroblasts and centrocytes and an increase in the number of small lymphocytes. In the IV phase, the content of centroblasts is reduced to 25.15%, the centrocyte is 30.04%, the small lymphocyte increases to 33.76%, the macrophage is 2.98%.
• V phase - progressive transformation of the germinative center. In the V phase of development of the germinal center, the centroblasts are contained in a small amount, amounting to 3.03%; the number of centrocytes decreases to 10.08%, small lymphocytes predominate, the level of which increases to 75.56%. In the mass of small lymphocytes, other cellular elements are lost.
• Phase VI - regressive transformation of the germinal center. In the VI phase, the germinal center is slightly expressed. Stromal cells predominate, accounting for 93.01% of all cellular elements of the germinal center. Small lymphocytes are few.

The content of immunoblasts in all phases varies from 1.0% to 0. A well-developed model of the "starry sky" was observed in I, II, III, IV and V phases.

In the mantle zone, the ratio of cellular elements is more stable: small lymphocytes predominate. However, cyclic changes are also observed in this zone: a gradual decrease in the concentration of central and small lymphocytes, most pronounced in phase VI, an increase in the content of stromal cells.

In the case of benign hyperplasia of lymphoid follicles in general variable immunodeficiency, in contrast to the cycle of germinal centers, there is normally no zonal distribution of centroblasts and centrocytes in the germinative center, the "starry sky" is not an independent phase, the phase of progressive and regressive transformation of the germinal center is characteristic, which is observed in nonspecific lymphadenitis in humans.

Phase VI benign nodular lymphoid hyperplasia often develops in patients with severe forms of general variable immunodeficiency, being a prognostically unfavorable sign.

With a general variable immunodeficiency with benign nodular lymphoid hyperplasia, the secretory immune system suffers.

There is a definite relationship between the number, prevalence, phases of development of lymphoid follicles of benign knot lymphoid hyperplasia, and the severity of the clinical picture of the disease.

With a general variable immunodeficiency, accompanied by the development of benign nodal lymphoid hyperplasia or without it, patients should receive replacement therapy with y-globulin throughout their life, with a syndrome of impaired absorption without mucosal atrophy - diet No. 4-4c. Treatment of chronic diarrhea is carried out by correction of metabolic disorders. Assign repeated courses of antibiotic therapy, with indications - courses of treatment of Giardiasis.

Cyclicity in the development of benign nodal lymphoid hyperplasia dictates the need for early diagnosis of general variable immunodeficiency with mandatory endoscopic examination of the small intestine and subsequent morpho-functional analysis.

Benign nodular lymphoid hyperplasia, being a frequent companion of the general variable immunodeficiency, can also develop with the pathology of the small intestine with an increased content of immunoglobulins in the blood serum, but it has a number of clinical and morphological features.

Patients with abdominal discomfort, diarrhea, imbalance in the immune system, accompanied by the development of benign knot lymphoid hyperplasia of the small intestine, should be examined more thoroughly and comprehensively.