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

Benign nodular lymphoid hyperplasia of the small intestine in common variable immunodeficiency

In the problem of small intestinal pathology, 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.

Due to close contact with antigens, powerful lymphoid tissue develops in the mucous membrane of the small intestine, forming an immunocompetent system in which cellular reactions occur, as well as sensitization of lymphocytes with subsequent differentiation into plasma cells that synthesize immunoglobulins.

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

The lymphoid tissue of the small intestinal wall is represented by the following structures located at various anatomical levels: intraepithelial lymphocytes localized between the enterocytes of the epithelium of the villi and crypts of the mucous membrane; lymphocytes that are part of its proper 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 lymphocytes of the lamina propria of the mucous membrane, which can migrate through the basement membrane of the integumentary epithelium in both directions and sometimes enter the intestinal lumen. Intraepithelial lymphocytes normally make up about 20% of all cells of the integumentary epithelium of the small intestinal mucosa. On average, there are 20 intraepithelial lymphocytes per 100 enterocytes in the jejunum and 13 lymphocytes in the ileum. P. van den Brande et al. (1988), when studying material taken from the ileum, found in control preparations that intraepithelial lymphocytes are mainly T-lymphocytes (T-suppressors), and rarely B-forms. According to the data cited by L. Yeager (1990), intraepithelial lymphocytes are represented by T-cells, of which 80-90% of the cells are T-suppressors, individual cells had a marker of NK-cells, 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, influencing the process of immunoglobulin synthesis by B-cells of the stroma of the lamina propria of the mucous membrane. Their cytotoxic potential is relatively low.

The number of lymphocytes diffusely located in the stroma of the lamina propria of the small intestinal mucosa in a healthy person is 500-1100 cells per 1 mm ² of area. They include B- and T-lymphocytes, and “zero” cells have also been found. Among B-lymphocytes, cells synthesizing IgA predominate. In a normal intestinal mucosa, about 80% of plasma cells synthesize IgA, 16% - IgM, about 5% - IgG. T-lymphocytes are represented mainly by T-helpers and T-suppressors, with a predominance of T-helpers in the unchanged mucosa.

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

Above the group lymphoid follicles there is a "vault" - a hemispherical area of the mucous membrane, in the area of which there are no villi and the number of goblet cells is sharply reduced. A structural feature of the epithelium covering the "vault" is the presence of specialized M-cells, on the apical surface of which there are no microvilli, glycocalyx, and in the cytoplasm - a terminal network and lysosomes. The development of microfolds instead of microvilli is characteristic, based on peculiar outgrowths and convolutions. M-cells are in close spatial connection with intraepithelial lymphocytes, which are contained in large folds of the cytolemma or its pockets, extending from the basal surface of M-cells. There is close contact between M-cells and nearby bordered enterocytes, as well as with macrophages and lymphocytes of the proper plate of the mucous membrane. M-cells are capable of pronounced pinocytosis and participate in the transport of macromolecules from the intestinal cavity to Peyer's patches. The main function of M-cells is the reception and transport of antigens, i.e. they play the role of specialized cells that ensure the absorption of antigens.

According to P. van den Brande et al. (1988), the germinal center of the Peyer's patch follicles 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 there are significantly more T-helpers than T-suppressors. Peyer's patch lymphocytes do not have killer properties. There is also evidence that Peyer's patch B-cells are not capable of producing antibodies. This feature may be due to the low content of macrophages in their germinal centers. However, Peyer's patch 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 patches and stimulate antigen-reactive lymphocytes. After activation, lymphocytes with lymph pass through the mesenteric lymph nodes, enter the blood and the proper plate of the small intestine mucosa, where they are transformed into effector cells that produce immunoglobulins, mainly IgA, and protect large areas of the intestine by synthesizing antibodies. Similar cells migrate to other organs. In Peyer's patches, of all the cellular elements that make up their structure, 55% are B-lymphocytes, in the peripheral blood they are 30%, in the spleen - 40%, in the red bone marrow - 40%, in the lymph nodes - 25%, in the thymus gland - only 0.2%. Such a high content of B-lymphocytes in group lymphoid follicles indicates the leading role of Peyer's patches in the production of B-lymphocytes.

Solitary lymphoid follicles of the small intestinal mucosa are not closely associated with the epithelium. They include B-lymphocytes, T-lymphocytes and macrophages. The functional features have not been sufficiently studied to date.

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

Infection of the mucous membranes by viruses and bacteria begins with their adhesion to the epithelial cells of the integumentary epithelium. The protective function in external secretions 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 contained in the secretions of all exocrine glands: milk, saliva, gastrointestinal secretions, secretions of the mucous membranes of the respiratory tract (nasal, pharyngeal, tracheobronchial), in tear fluid, sweat, and secretions of the genitourinary system.

Secretory IgA is a complex consisting of a dimer, a molecule of the secretory component that protects SIgA from proteolysis, and a molecule of the J-chain. The J-chain (joining) is a cysteine-rich polypeptide with a molecular weight of 15,000. The J-chain is synthesized, like IgA, primarily by plasma cells of the lamina propria of the small intestinal mucosa. The 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 acts as an active barrier to the introduction of foreign antigens. In a healthy person, its work is harmonious and fully ensures the protection of the body from the action of pathogenic factors. However, in pathology, in particular with the development of general variable immunodeficiency with a predominance of a lack of antibody production, in response to intense antigen stimulation in the mucous membrane of the small intestine and in some cases in the antral section of the stomach and colon, an additional structure develops - benign nodular lymphoid hyperplasia, introducing a certain correlation into the synthesis of immunoglobulins due to the release of a large number of lymphocytes into the stroma of the proper plate of the mucous membrane.

According to the histological classification of intestinal tumors by WHO, adopted in Geneva in 1981, nodular lymphoid hyperplasia is classified as a benign tumor-like lesion that has the appearance of multiple polypoid formations in the mucous membrane of the small intestine, which are based on reactive hyperplastic lymphoid tissue (Geneva, 1981).

For the first time in 1958, V. G. Fircin and C. R. Blackborn discovered numerous nodules in the mucous membrane of the small intestine during autopsy, the basis of which was lymphoid tissue.

Benign nodular lymphoid hyperplasia is characterized by a clear endoscopic picture, distinct radiological signs, certain morphological criteria and clinical features of the disease.

More recently, researchers have drawn attention to the connection between the development of benign nodular lymphoid hyperplasia and common variable immunodeficiency.

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

Macroscopically, benign nodular lymphoid hyperplasia appears as multiple, non-pedunculated, polypoid structures ranging in diameter from 0.2 to 0.5 cm, protruding above the surface of the small intestinal mucosa.

Benign nodular lymphoid hyperplasia is usually an endoscopic finding, appearing as nodules against the background of hyperemic mucosa of the small intestine.

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

In recent years, in our country and abroad, much attention has been paid to the study of immunodeficiency states, in which both isolated defects in the cellular and humoral links of immunity, as well as their combination, are observed.

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

Currently, a number of authors also use the terms “late-onset common variable acquired hypogammaglobulinemia”.

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

• immunodeficiency with a predominance of antibody defects;
• combined immunodeficiency;
• immunodeficiency due to other major defects;
• complement deficiency;
• defects in phagocyte function.

Common variable immunodeficiency (common variabeliti immunodeficiency) is classified as a combined immunodeficiency and is subdivided into common variable immunodeficiency with a predominance of cellular immunity deficiency and with a predominance of antibody deficiency.

General variable immunodeficiency with a predominance of antibody deficiency, accompanied by the development of benign nodular lymphoid hyperplasia of the small intestine, is a major clinical problem, since, on the one hand, nodular lymphoid hyperplasia, being a reactive formation, to some extent helps to compensate for the lack of antibody synthesis in the context of developed immunodeficiency, especially in its early stages, and on the other hand, it itself can become a source of development of malignant neoplasms - lymphomas of the gastrointestinal tract.

The clinical picture of benign nodular lymphoid hyperplasia of the small intestine in patients with common variable immunodeficiency with predominant antibody deficiency includes all the symptoms of this immunological deficiency syndrome and signs inherent in nodular lymphoid hyperplasia.

Patients report pain in the abdominal area, mainly around the navel. With a significant increase in the number of lymphoid nodules, the pain becomes paroxysmal, and due to periodic intussusception, intestinal obstruction may 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, and the loss of body weight is 7.33±3.8 kg. A connection has been established between the development of nodular lymphoid hyperplasia and giardiasis. This group of patients has an increased risk of developing malignant tumors.

During periods of exacerbation of the disease, patients note increased fatigue, general weakness, decreased or complete loss of ability to work.

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

Characteristic are recurrent chronic diseases of the respiratory system: repeated pneumonia, repeated tracheobronchitis, as well as sinusitis, otitis, cystitis, chronic pyelonephritis, furunculosis. With a long course of the disease, pulmonary emphysema and pneumosclerosis may develop. One of the main symptoms is the occurrence of splenomegaly.

The results of recent studies suggest that immunodeficiencies are accompanied by such autoimmune diseases as hemolytic and pernicious anemia, autoimmune neutropenia, thrombocytopenic purpura. Connective tissue is also affected: dermatomyositis, scleroderma, rheumatoid arthritis may develop. In the case of antibody deficiency syndrome, sensitivity to encephalitis and meningitis viruses is high.

Most often, general variable immunodeficiency is accompanied by malabsorption syndrome of varying severity (in 35-95% of cases), often grades II and III. The development of grade III malabsorption syndrome is accompanied by significant weight loss, hypoproteinemic edema, anemia, hypocalcemic tetany, osteomalacia, hypercatabolic exudative enteropathy, decreased absorption of vitamin B12 and electrolytes.

Diagnosis of intestinal nodular lymphoid hyperplasia

One of the main signs of the disease is a decrease in the content of all three classes of immunoglobulins (A, M, G) in the blood serum, especially significant for class A, which performs the main barrier function in protecting the mucous membrane from the penetration of foreign antigens into the internal environment of the body. In this form of immunodeficiency with nodular lymphoid hyperplasia, a number of patients showed significant fluctuations in the content of various immunoglobulins, detected by the Mancini radial immunodiffusion method. However, the use of nonparametric criteria in mathematical processing, in particular Kruskal-Wallace, made it possible to identify a general pattern in the change in these indicators: a decrease in the IgA level to 36.16% of the control taken as 100% (p = 0.001), a decrease in the content of IgM to 90.54% (p = 0.002) and IgG to 87.59% (p = 0.001) of the control values taken as 100%.

Mathematical processing of laboratory data from 44 patients with nodular lymphoid hyperplasia and common variable immunodeficiency revealed an increase in the lymphocyte content in the peripheral blood to 110.11% (p = 0.002) compared to the control, which was taken as 100%.

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

During immunological examination of patients with benign nodular lymphoid hyperplasia, the total number of T-lymphocytes in the peripheral blood was reduced due to a decrease in the content of T-helpers. An increase in the number of T-suppressors was observed, which can lead to an imbalance in the CD4/CD8 ratio.

The study of the protein spectrum of the blood showed that nodular lymphoid hyperplasia and general variable immunodeficiency are characterized by a statistically significant increase in the content of a-globulins to 141.57% (p = 0.001), beta-globulins - to 125.99% (p = 0.001) compared to the control values taken as 100%. Mathematical processing made it possible to identify a statistically significant decrease in the content of a-globulins, y-globulins, bilirubin and cholesterol in the blood. The sugar curve was distinguished by a more reduced increase in blood sugar after exercise, characteristic of the syndrome of impaired absorption, compared to the norm.

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

In general variable immunodeficiency, lymphoid nodules may be localized in the mucous membrane of one, two, or all three sections of the small intestine. Sometimes the antrum of the stomach and the colon are involved in the process.

Lymphoid follicles are located directly under the integumentary epithelium, near the basement membrane, or in the superficial layers of the lamina propria of the small intestinal mucosa. From the mantle zone of the follicles toward the integumentary epithelium, lymphocyte migration in the form of lymphoid tracks is noted. In the lamina propria zone, located between the epithelium and follicles, B-lymphocytes are concentrated, as well as T-lymphocytes of two subtypes: T-helpers and T-suppressors, of which T-suppressors predominate in general variable immunodeficiency.

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

In these areas, a significant increase in the height of the bordered enterocytes was noted, reaching 52.5±5.0 μkt. Goblet cells were single. However, specialization of enterocytes in the locations of lymphoid follicles was not observed. A significant increase in the number of intraepithelial lymphocytes, represented by T-suppressors, was noted.

The results of studying light-optical preparations obtained from biopsy specimens taken from various sections of the small intestine showed that in nodular lymphoid hyperplasia and general variable immunodeficiency, thinning of the brush border of enterocytes, a decrease in the content of neutral glycosaminoglycans in it, and dystrophic changes in the cytoplasm were observed. In the stroma of the lamina propria of the mucous membrane, against the background of an increased content of small lymphocytes and eosinophils, a decrease in the number of plasmatic and lymphoplasmacytoid cells is observed, especially pronounced in severe general variable immunodeficiency.

Simultaneous electron microscopic examination of biopsy specimens of the duodenum, jejunum and ileum mucosa revealed uniform changes in the limbic enterocytes of the villi. On the apical surface of a number of enterocytes, shortening and rarefaction of the microvilli, their irregular arrangement, and local disappearance were noted, with the development of grade III malabsorption syndrome. Glycocalyx on the surface of the microvilli was found in insignificant quantities, and in some places it was completely absent. In the cytoplasm of many enterocytes, signs of disorganization of varying degrees were revealed: expansion of the canals of the granular and agranular cytoplasmic reticulum, swelling of the mitochondria with a decrease in the number of cristae in their matrix and the formation of myelin-like structures, hypertrophy of the lamellar complex.

Lymphoid follicles are formed by germinal centers (follicular, clear centers) and mantle zones. Germinal centers were often expanded. According to the classification of K. Lennert (1978), they include 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 cellular elements. When studying the cellular composition of lymphoid follicles using monoclonal antibodies in benign nodular lymphoid hyperplasia and common 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 there were most T-suppressors. T-suppressors were also predominant around the follicles.

However, AD B. Webster (1987) found IgM in jejunal juice, and IgM-containing cells in the lamina propria of the small intestinal mucosa; a decrease in the intensity of luminescence of plasma cells containing IgA, IgM, and IgG was also noted in patients with common variable immunodeficiency with nodular lymphoid hyperplasia, which indicates an incomplete block in the differentiation of B-lymphocytes. The assumption that in the area around the follicles, the maturation of B-lymphocytes to plasma cells capable of producing immunoglobulins is suppressed by T-suppressors is substantiated.

The results of morphometry of cellular elements of follicles of benign nodular lymphoid hyperplasia using the method of calibrated squares with subsequent mathematical processing allowed us to identify the cyclicity of changes in germinal centers and mantle zones, including 6 main phases of development. The following phases are distinguished in the germinal zones:

• Phase I - predominance of centroblasts. In phase I, centroblasts make up 80% of all cellular elements of the center, centrocytes - 3.03%, macrophages - 5.00%.
• Phase II - a decrease in the content of centroblasts and an increase in the number of centrocytes. In phase II, the number of centroblasts decreases to 59.96%, centrocytes increases to 22.00%, small lymphocytes - to 7.09%.
• Phase III - equal content of centrocytes and centroblasts. In phase III, the number of centroblasts is 39.99%, centrocytes - 40.0%, small lymphocytes - 9.93%, macrophages - 3.53%.
• Phase IV - a decrease in the content of centroblasts and centrocytes and an increase in the number of small lymphocytes. In phase IV, the content of centroblasts decreases to 25.15%, centrocytes are 30.04%, small lymphocytes increase to 33.76%, and macrophages are 2.98%.
• Phase V is a progressive transformation of the germinal center. In phase V of the development of the germinal center, centroblasts are present in small quantities, constituting 3.03%; the number of centrocytes decreases to 10.08%, small lymphocytes predominate, the level of which increases to 75.56%. Other cellular elements are lost in the mass of small lymphocytes.
• Phase VI - regressive transformation of the germinal center. In phase VI, the germinal center is expressed slightly. Stromal cells predominate, making up 93.01% of all cellular elements of the germinal center. Small lymphocytes are few in number.

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

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 content of centroblasts and small lymphocytes, most pronounced in phase VI, an increase in the content of stromal cells.

In 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 germinal center, the “starry sky” is not an independent phase, a phase of progressive and regressive transformation of the germinal center is characteristic, which is observed in nonspecific lymphadenitis in humans.

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

In common variable immunodeficiency with benign nodular lymphoid hyperplasia, the secretory immune system is affected.

A certain relationship is observed between the number, prevalence, phases of development of lymphoid follicles of benign nodular lymphoid hyperplasia and the severity of the clinical picture of the disease.

In general variable immunodeficiency, accompanied by the development of benign nodular lymphoid hyperplasia or without it, patients should receive lifelong replacement therapy with y-globulin, in case of malabsorption syndrome without mucosal atrophy - diet No. 4-4B. Chronic diarrhea is treated by correcting metabolic disorders. Repeated courses of antibacterial therapy are prescribed, if indicated - courses of treatment for giardiasis.

The cyclical nature of the development of benign nodular lymphoid hyperplasia dictates the need for early diagnosis of common variable immunodeficiency with mandatory endoscopic examination of the small intestine and subsequent morphofunctional analysis.

Benign nodular lymphoid hyperplasia, being a frequent companion of common variable immunodeficiency, can also develop in 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, and imbalance in the immune system, accompanied by the development of benign nodular lymphoid hyperplasia of the small intestine, should be examined more thoroughly and comprehensively.