[Immunological aspects of tuberculosis pathogenesis].

The morphological aspects of TB pathogenesis are well described in the publications. Much is also known about the main stages of development and formation of specific adaptive immunity. However, from our point of view, not enough attention is being paid to the involvement of the immune system in the pathogenesis of clinically relevant TB abnormalities, as well as various forms of the disease. Nevertheless, there is no doubt that the variety of clinical manifestations of any disease associated with the penetration of a foreign agent into the body, and Mycobacterium tuberculosis (MTB) in particular, is due to the collective interaction of the infectious agent and the individual response of the macroorganism to this infectious agent. The mosaic of such interactions usually imposes its own adjustments on the development of different forms of the process, its speed and direction, as well as the outcomes. Certainly, the response of a macroorganism to MTB is an integral part of pathogenesis and consists of many general components including the responses associated with the mechanisms of natural and acquired immunity. Intensity of these reactions depends on the characteristics of an agent (MTB) and a macroorganism. For the development of TB disease, massiveness of TB infection, dose and duration of MTB exposure to the human body, as well as virulence of MTB and the level of body's protection during the exposure play a very important role. TB pathogenesis is somewhat different in primary MTB infection and re - infection. With primary infection, 88-90% of individuals do not have clinical manifestations, and only the tuberculin skin test conversion signals the onset of infection. In some cases, without any use of anti-TB drugs limited abnormalities may result in spontaneous cure with the minimal residual changes in the lungs, intrathoracic lymph nodes and tissues of other organs, often in the form of calcifications and limited areas of fibrosis in more advanced cases. Only 10-12% of newly infected individuals develop TB with severe clinical manifestations requiring TB therapy. The absence of clinical manifestations of primary TB infection can be explained by a high level of natural resistance of the human body to tuberculosis, and sometimes can be an effect of acquired protection due to BCG vaccination. This review attempts to discuss the role of immune mechanisms in the pathogenesis both at the beginning of disease development, and in the process of its various manifestations. Issues of genetically determined resistance or susceptibility to TB are not being covered in detail in this manuscript.

[A locus involved in tuberculosis infection control in mice locates in the proximal part of the H2 complex].

One of genetic loci involved in tuberculosis (TB) infection control in mice is located within the segment of Chr. 17 occupied by the H2 complex, the mouse MHC. As far as this region includes approximately 40 Mb and contains hundreds of genes affecting immune responses and host-parasite interactions, narrowing the interval by genetic recombination is pre-requisite for identification of particular gene(s). We have developed a panel of recombinant congenic strains bearing different parts of the H2 complex from TB-susceptible I/St mice on the genetic background of TB-resistant C57BL/6 mice. By superposing the phenotype "severe vs. mild infectious course" against the chart of alleles inherited by these new strains from the two parental strains, we have mapped a locus involved in TB control within the segment 33.305-34.479 Mb (-1.1 Mb) of the Chr. 17. Such a location indicates that allelic variants of the prominent pro-inflammatory factor TNF do not affect TB course in our experimental system. This result was confirmed by the assessment of the TNF level in the lung tissue of infected mice of different strains. The QTL (quantitative trait locus) mapped in our study influences several important parameters of TB infection: multiplication of mycobacteria in the lungs, severity of lung pathology and regulation of the early inflammatory response.

[Immunomorphological characteristics of experimental granulomatous inflammation caused by Mycobacterium avium].

The results of the topical arrangement of T and B lymphocytes in the lung tissue granulomatous masses of the mice susceptible (C57BL/6Ycit) and resistant (I/StSnEgYCit) to aerosol inoculation with M. avium 724R in a dose of 2 x 10(3) CFU/mice are presented by means of labeled monoclonal antibodies. At week 8 of the inoculation, CD4+ lymphocytes were located both among the granuloma cells in the diffuse fashion and as small clusters and in the interalveolar and interlobular septa in the B6 mice and these were mainly in the granuloma in the I/St mice. At week 16, CD8+ lymphocytes were found in the peripheral granuloma portions in the B6 mice and these were diffusely throughout the area of granulomatous masses in the I/St mice. In the B6 mice, CD19+ lymphocytes formed cell aggregates from week 8 of the inoculation; and in the I/st mice, these were diffusely located among the granuloma cells and abundantly in the interalveolar and interlohular septa.

[Tuberculin diagnosis in children with a family history of allergy].

Two hundred and eighteen Mycobacterium tuberculosis-infected children and adolescents aged 4 to 18 years were examined. Whether the patients and their relatives had a history of allergic reactions was ascertained. A complex of diagnostic studies is of great value in verifying the presence of concomitant allergic diseases. The rate of allergic reactions in the child's history does not itself determine the likelihood of development of allergic states. The Mantoux (tuberculin) test in allergic children does not lead to an exacerbation of the underlying disease at remission. The remission manifestations of paraallergy are noted in 15.8% of the patients with allergic diseases and in 42.9% of the children having allergic reactions in the history. This supports the quality of a follow-up and treatment by an allergist, as well as an adequate response to a Mantoux test with 2 TE of PPD-L in the bulk of allergic children. The use of antihistamines as preparation for the test allows an inference about true infection and the sensitivity to tuberculin in both the most of allergic patients and persons with a history of allergic manifestations.

[Experience with bronchomunal used in the combined treatment of patients with bronchial asthma and chronic obstructive pulmonary disease].

The paper presents the results of treatment in 30 patients aged 16-59 years who have bronchial asthma and chronic obstructive pulmonary disease, by using a bacterial vaccine (bronchomunal) containing antigens of opportunistic bacteria: Streptococcus pneumoniae, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus viridans, Streptococcus piogenes, Moraxella catarrhalis. Immunotherapy with the vaccine had good and excellent effects in 73.33 of cases; the mean duration of acute respiratory viral infection decreased from 16 to 9 days after vaccination and a need for antibiotics. In the comparison group, a good effect was noted in 40% of the patients during one-year follow-up; the difference was statistically significant. The vaccine's tolerance was good; only 3 (9.9%) patients were observed to have vaccination-induced complications: exacerbations of chronic maxillary sinusitis and chronic bronchitis in 2 and 1 patients, respectively. The positive effect of bronchomunal was associated with the better values of cellular immunity, stabilized phagocytosis, and lower IgE levels.

I/St mice hypersusceptible to Mycobacterium tuberculosis are resistant to M. avium.

We previously demonstrated that mice of the I/St strain are extremely susceptible to Mycobacterium tuberculosis, as well as to the taxonomically distant intracellular bacteria Chlamydia pneumoniae and Salmonella enterica. To broaden our knowledge about the control of susceptibility to intracellular pathogens, we studied the infection caused by Mycobacterium avium virulent strain 724 in a panel of inbred mouse strains and found that I/St mice are resistant to M. avium. By comparing I/St mice with B6 mice, we demonstrated that (i) B6 mice are much more susceptible to infection caused by M. avium in terms of bacterial multiplication in the lung tissue and severity of lung pathology; (ii) in B6 mice but not in I/St mice infection leads to prolonged leukocyte infiltration of the lung tissue, development of necrotic lung granulomata, and lethality; and (iii) the unfavorable infectious course in B6 mice is accompanied by elevated production of gamma interferon, tumor necrosis factor alpha, and especially interleukin-12 in the lungs. Importantly, M. avium-resistant I/St mice carry a functional r allele of the Slc11a1 (formerly Nramp1) gene, while B6 mice have the Slc11a1(s) genotype. Segregation genetic analysis of (I/St x B6) F2 hybrids demonstrated that susceptibility or resistance to infection caused by M. avium largely depended upon the Slc11a1 genotype and that other genetic traits had a relatively weak influence. This close-to-monogenic pattern differs sharply from the host control of many other intracellular bacterial infections, for which the involvement of numerous quantitative trait loci has been ubiquitously observed.

[Role of specific immunoglobulins of classes G, E and subclasses G1, G4 in the diagnosis of tuberculosis in children with hyperergic tuberculin sensitivity].

The study covered 56 patients (aged 6-14 years) having hyperergic tuberculin sensitivity, including 28 patients with pulmonary tuberculosis (Group 1) and 28 patients infected with Mycobacterium tuberculosis (MBT) (Group 2). All tuberculous processes were asymptomatic and limited. Minor forms of tuberculosis, diagnosed by computed tomography, were found in 71.4% of cases. The signs of incomplete calcification were detectable in 93% of cases. In the past year, tuberculin sensitivity has progressed to hyperergic one in 75% of Group 2 patients. The patients with tuberculosis were treated with 3 drugs; those infected with M BT received 2 agents. In the patients with minor forms of tuberculosis, the level of specific IgG antibodies was equal to those in healthy MBT-infected individuals with hyperergic tuberculin sensitivity, the levels of immunoglobulins of subclasses G1 and G4 were lower, that of IgE antibodies were higher than in the MTB-infected. These data may suggest the stability of the immune system in patients with minor forms of tuberculosis, detected in the phase of calcification, and its instability in the MBT-infected with tuberculin sensitivity increasing up to hyperergic one.

Direct comparison of low-dose and Cornell-like models of chronic and reactivation tuberculosis in genetically susceptible I/St and resistant B6 mice.

We applied the low-dose challenge (chronic) and reactivation following chemotherapy withdrawal (Cornell-like) TB models to mouse strains with genetically different susceptibility to and severity of Mycobacterium tuberculosis-triggered disease. Systemic infection caused by intravenous (i.v.) administration of approximately 70 cfus of M. tuberculosis H37Rv lead to chronic, persistent, non-lethal disease in genetically resistant B6 mice, but resulted in a fatal pathological process in the lungs of susceptible I/St animals. Thus, application of the identical experimental approach to genetically different murine hosts allows investigating both slowly progressive disease with the fatal outcome (I/St) and chronic life-span disease (B6). Under Cornell-like model conditions, both temporary eradication of cultivable bacilli from lungs and spleens due to chemotherapy and their re-appearance in organs following its withdrawal were demonstrated in mice of both strains. However, (i) reactivation occurred significantly earlier in I/St than in B6 mice; (ii) I/St mice survived not more than 6 month following chemotherapy withdrawal and demonstrated 100% TB relapse, whereas in B6 mice mortality did not exceed 50%, and no mycobacteria were recovered from some animals. I/St mice, with their genetically determined high TB severity, provide a more reliable tool for modeling TB relapse after chemotherapy withdrawal than mice of more resistant strains.

[Tuberculous IgE antibodies. Part II. Study of its concentrations in different forms of tuberculosis]. / Protivotuberkuleznye IgE-antitela. Chast' II. Issledovanie kontsentratsii pri razlichnykh formakh tuberkuleza.

Tuberculosis-afflicted lung are infiltrated by two functionally types of lymphocytes, which presumably counteract with each other by producing proinflammatory (type 1) and anti-inflammatory (type 2) cytokines. It is held that irregular sequestration of antigen into different compartments of the lung may lead to preferential activation of T-helper 1 or T-helper 2 lymphocytes. Unlike IgE antibodies, specific tuberculosis IgE antibodies are seen only in tuberculosis infection. The mean values of IgE antibodies in tuberculosis (7.661 +/- 0.849 IU/ml) are significantly greater than those in other pulmonary diseases (1.768 +/- 0.116 IU/ml). Low concentrations of tuberculosis IgE antibodies in persons with a marked hyperergic response to tuberculin (1.808 +/- 0.097 IU/ml) are of importance. Significant concentrations of mycobacterial IgE antibodies are mainly detected in fibrocavernous (14.56 +/- 1.11 IU/ml), infiltrative (10.10 +/- 1.08 IU/ml), peripheral lymph nodal (10.53 +/- 1.09 IU/ml) tuberculosis rather than intrathoracic lymph nodal tuberculosis (4.555 +/- 0.340 IU/ml). There is a particularly considerable increase in specific IgE antibodies in a phase of decay (15.98 +/- 1.64 IU/ml) and infiltration (12.66 +/- 1.08 IU/ml). These groups also show a concurrent rise in tuberculosis IgG antibodies, which nevertheless disagree with the increase of IgE (the correlation coefficient is 0.599).

[Anti-tuberculous IgE antibodies. I. Immunodominant antigens]. / Protivotuberkuleznye IgE-antitela. I chast'. Immunodominantnye antigeny.

It is widely accepted that protection against tuberculosis is provided by the formation of type 1 immune response, which is characterized by the production of IFN-gamma and IL-2. However, type 2 antimycobacterial immune response is also present: specific IgE antibodies that are IL-4 dependent, are usually found in tuberculosis patients. There is elevated production of type 2 cytokines in some cases. Thus, both types of an immune response can simultaneously develop, probably counteracting with each other. It is unknown which of mycobacterial antigens are capable of inducing a preferential type 2 response. To detect these antigens, the authors studied tuberculosis IgE antibodies in the sera of 500 tuberculosis patients by using the ELISA assay with ultrasonic disintegrated M. Tuberculosis H37Rv (sonicate). Antigens recognized by IgE antibodies were found to be localized in the cell wall of mycobacteria. The IgE-response was specific since the sera did not react with the antigens of atypical mycobacteria and other bacterial species.

Comparative analysis of mycobacterial infections in susceptible I/St and resistant A/Sn inbred mice.

SETTING: The availability and appropriate use of animal models is of significant importance for a better and more detailed understanding of the genetic, immunological and pathological mechanisms underlying the development of mycobacterial disease in humans. OBJECTIVE: To define a mouse model for tuberculosis severity that can be easily adapted to genetic and immunological analysis of host response to Mycobacterium tuberculosis infection. DESIGN: We describe here two inbred strains of mice, I/St and A/Sn (both Nramp1'), that differ vastly in commonly used parameters of susceptibility to infection with virulent and attenuated strains of M. tuberculosis. RESULTS: Following infection with a high dose of virulent H37Rv. M. tuberculosis and compared to their resistant A/Sn counterparts, I/St mice displayed more than a 2-fold shorter mean survival time and a more rapid onset and progression of severe body weight loss (cachexia). Moreover, I/St mice supported 20-100-fold higher multiplication of M. tuberculosis following challenge with H37Rv over a large range of infectious inocula. The high susceptibility of I/St mice was also reflected by more severe lung histopathology as evidenced by larger and more numerous lung granuloma and macrophage dominated cellular infiltrates. Finally, we determined that I/St are also unable to control infection with attenuated H37Ra M. tuberculosis and two strains of M. bovis (BCG and Ravenel) indicating hyper-susceptibility of the I/St mouse strain to mycobacterial infections. CONCLUSIONS: The results of our experiments suggest that comparative analysis of resistant A/Sn and susceptible I/St mice provides an ideal way to study host dependent aspects of tuberculosis susceptibility under the controlled conditions provided by an animal model.

[The indices of interleukin 1, 2 and 4 production and the specific antibody titers in mice with an opposite sensitivity to staphylococcal infection]. / Pokazateli produktsii interleikinov 1, 2 i 4 i titry spetsificheskikh antitel u myshei s oppozitnoi chuvstvitel'nost'iu k stafilokokkovoi infektsii.

The data on a high level of interleukin production in mice, resistant to staphylococcal infection (CBA), in comparison with that in mice, sensitive to this infection (C3HA), are presented. The production of interleukin 1 in intact and infected mice of different strains exhibited no differences between these strains, but its level considerably increased after the inoculation of the animals. A the same time differences in the synthesis of IgM and IgG1 in intact and infected mice of different strains were noted.

[Mouse genes that control tumor growth and tuberculous infection]. / Geny myshi, kontroliruiushchie rost opukholi i tuberkuleznuiu infektsiiu.

The paper presents some experimental data and speculations about antituberculous resistance and immunity in mouse mutants resisting spread of transplantable syngeneic tumor.

[The lymphocyte proliferative response to Staphylococcus aureus antigen in mice with an opposite susceptibility to staphylococcal infection]. / Proliferativnyi otvet limfotsitov na antigen Staphylococcus aureus u myshei s oppozitnoi chuvstvitel'nost'iu k stafilkokkovoi infektsii.

The difference between the proliferative response of spleen cells to S. aureus cytoplasmic antigen on days 5 and 9 of the infectious process was shown in experiments of CBA and C3HA mice, opposite in their susceptibility to systemic staphylococcal infection. Hybrid mice F1 (CBA x C3HA) inherited a high level of proliferative response on day 5 (as in resistant CBA mice) and its low level on day 9 (as in susceptible C3HA mice). These data on genetic differences in proliferative response to S. aureus cytoplasmic antigen were confirmed in the test of the proliferation of lymph node lymphocytes taken from mice of these lines immunized with the above-mentioned antigen in Freund incomplete adjuvant into the pad of their paws 14 days before the test.

[Immunity and resistance in experimental tuberculosis in mice exposed to various environmental factors]. / Immunitet i rezistentnost pri éksperimentalnom tuberkulëze u myshei, nakhodiashchikhsia v raznykh usloviiakh soderzhaniia.

CBA mice maintained on the chow and water with either normal or deficient in particular trace elements were infected with M. tuberculosis H37Rv. Mice with deficiency of silicon showed a tendency for decreased survival, had less active DTH response to tuberculin and proliferation in vitro upon stimulation by mycobacterial antigens and nonspecific mytogens than mice on balanced diet, higher levels of specific IgG. Addition of silicon to the diet of silicon-deficient mice corrected antituberculosis immunity.

[Cytokines in tuberculosis]. / Tsitokiny pri tuberkuleze.

The paper presents the data available in the literature and the authors' own findings concerning the production of cytokines, such as interleukins 1, 2, 4, 6, and 8, interferons and tumor necrosis factor, in patients with different stages of tuberculosis. A relationship between the production rate of some cytokines and the stage of the disease, the extent of the process, chemotherapeutical efficiency and other clinically important factors is discussed. The prospects of further investigations in this area are dealt with.