Immune responses in tuberculosis: antibodies and CD4‐CD8 lymphocytes with vascular adhesion molecules and cytokines (chemokines) cause a rapid antigen‐specific cell infiltration at sites of bacillus Calmette–Guérin reinfection

Abstract

SUMMARYRabbit primary dermal bacillus Calmette±Gue Ârin (BCG) lesions were compared with reinfection BCG lesions in order to gain insight into how immune responses protect against clinical tuberculosis. As early as 3 hr, a marked in®ltration of macrophages and lymphocytes occurred in the reinfection group, while very little cell in®ltration occurred in the primary group. It seems that only an antigen±antibody reaction could produce such an immediate pronounced antigen-speci®c chemotactic effect, because very few lymphocytes are normally present in the skin. Therefore, antibodies hasten the accumulation of an expanded antigen-speci®c T-lymphocyte population (memory cells) at sites of bacillary lodgement. By 1±2 days, the primary and reinfection BCG lesions differed 400-to 500-fold in size. By 4±5 days, the size of the reinfection lesions had declined, while the size of the primary lesions had increased, so that, grossly, both types of lesion were similar. At 8 days in reinfection lesions and at 12 days in primary lesions, small secondary peaks in size occurred, which were probably caused by cell-mediated immune responses. In rabbits with primary BCG lesions, skin tests with Old Tuberculin were positive at 9 days, accompanied by a rise in the levels of antibodies to the secreted antigen, phosphate-speci®c transport protein 1, but the levels of antibodies to the constitutive antigens, puri®ed protein derivative and heat-shock protein 65, did not increase appreciably until some time after 23 days. In tissue sections of reinfection BCG lesions, the percentage of mononuclear cells labelled, by in situ hybridization techniques, for the mRNA of monocyte chemoattractant protein 1 (MCP-1), a chemokine, peaked at 3 hr and then was down-regulated, whereas in primary lesions, this percentage was down-regulated only after 2 days.[The percentage in the tissue sections for the mRNAs of interleukins 1b and 8, as well as the proteins of MCP-1 and tumor necrosis factor alpha (TNF-a), followed a somewhat similar time-course to that of MCP-1 mRNA.] A high percentage of mononuclear cells containing the MCP-1 mRNÀ factory' would favour enlargement of the lesions and a low percentage would favour their regression. At 5 days, the percentage of CD4 and CD8 lymphocytes, stained by immunohistochemical techniques, and the amount of microvasculature stained similarly for vascular cell adhesion molecule 1 were higher in the reinfection group, indicating that prior immunization caused a more rapid (antigen-dependent) up-regulation of these factors. Tuberculin reactions resembled early reinfection BCG lesions in almost every factor evaluated herein. In brief, the production of chemokines began soon after BCG reinfection, peaked within a few hours and was markedly downregulated by 24 hr, a time at which the lesions of reinfection were of maximal size. Therefore, the amount of cell in®ltration was tightly controlled, probably by the variety of mechanisms listed herein.

Neutrophils in tuberculosis: friend or foe?

“…This was first reported in observational studies in animal models [14,15], and has since been confirmed by researchers studying various mycobacteria, animal host species and routes of infection [6,12,[16][17][18][19]. Accumulation happens quickly.…”

Expression ofl-Selectin (CD62L), CD44, and CD25 on Activated Bovine T Cells

“…Effective cytolytic activity of CD8 ϩ cells, unlike trafficking and IFN-␥ production by mycobacterium-specific CD8 ϩ cells, requires an intact CD4 ϩ cell population (49). CD8 ϩ and ␥␦ T cells respond to various mycobacterial antigens and also accumulate at sites of infection, suggesting sequential expression of appropriate adhesion molecules that favor trafficking to sites of inflammation induced by the mycobacterium (5,8,12,20,29,46,48,50,54). Indeed, activated (i.e., CD44 hi CD62L lo ) CD8 ϩ T cells are detected within the lungs of both tuberculous CD4…”

BCG-induced Rabbit Alveolar Macrophages are Endowed with Strengthened Antioxidant Metabolic Pathways

“…Cytokines are produced in large amount during the course of the BCG infection [44]. Figure 4b shows that TNFa production progressively increased during the infection period and reached its maximum value at 21st day.…”

“…After the first contact between pathogens and resident macrophages leading to cell death, lymphocyte activation, cytokine secretion and inflammation [28,29], the resident macrophage population should be rapidly substituted with another one, composed of activated macrophages armed with a powerful anti-mycobacterial armamentarium [1,30], which are expected to be resistant to mycobacterium-induced apoptosis. These cells may clear apoptotic bodies, and both kill residual pathogens and even new invaders, and hence represent the ultimate effector arm of the adaptive immunity.…”