Defense against extracellular bacteria
Humoral mechanisms and phagocytosis play a key role in combating extracellular bacteria.
Innate humoral response Natural IgM antibodies are the first to enter the fight. They recognize basic bacterial antigens (lipopolysaccharide, phosphorylcholine, peptidoglycan) and trigger the classical complement activation pathway. This leads to opsonization (potent stimulation of phagocytosis) or direct lysis of the pathogen (for example, in infections caused by neisseriae). Additionally, epithelial cells and phagocytes secrete defensins, and pentraxins help bind bacteria.
Adaptive humoral response Regardless of the success of innate defense, dendritic cells capture antigens (including exotoxins) and migrate to regional lymph nodes to present them to CD4+ T lymphocytes.
- The response is dominated by the activation of Th2 cells (whereas Th17 mobilize neutrophils, and Th1 are responsible for the IFNγ-dependent part of the response).
- B lymphocytes recognize the antigen, present it to Th2 cells, and receive a co-stimulatory signal via the CD40 receptor.
- Clonal proliferation of B cells is driven by the cytokine IL-4.
- In the germinal centers of lymphoid follicles (with the participation of follicular dendritic cells and CXCR5+ T helper cells), the affinity of the B-cell receptor increases and its isotype switching occurs.
The generated plasma cells migrate to the bone marrow, the red pulp of the spleen, or the medullary cords of the lymph nodes, secreting highly specific antibodies. IgA dominates on mucous membranes. Antibodies are able to independently neutralize toxins in the intestinal lumen, immobilize bacteria (anti-flagellar antibodies), and multiply enhance phagocytosis.
Survival mechanisms of intracellular pathogens
Defense against intracellular bacteria is examined using the classic example of Mycobacterium tuberculosis. Entering the body via airborne droplets, they interact with alveolar macrophages. TLR-2 and TLR-4 receptors recognize components of the bacterial cell wall. However, mycobacteria use the virulence factor lipoarabinomannan (LAM), which, by binding to mannose residues, blocks intracellular signal transduction from TLRs.
Incomplete phagocytosis develops—a state in which the macrophage has engulfed the bacterium, but the pathogen remains viable due to a number of blocks:
- Fusion of the phagosome with the lysosome is disrupted (the necessary EEA1 factor is missing).
- The work of V-ATPase is blocked, causing the pH inside the phagosome to remain at 6.0–6.3 (whereas digestion requires pH 5.0).
- Acid hydrolases and cathepsin D are not activated in endosomes.
- The calcium response is suppressed.
- Signaling cascades are blocked (via the $PI_3K$ kinase, as well as the ERK1/2 and p38 factors).
In addition, mycobacteria induce the anti-apoptotic protein Bcl-2, artificially prolonging the life of the infected macrophage, which loses its bactericidal activity and turns into a safe reservoir for the pathogen.
Effector link and destruction of intracellular pathogens
To eliminate the infection persisting within macrophages, induction of a robust cellular response is required. Dendritic cells endocytose bacterial fragments and migrate to lymph nodes. Their activation via TLR-2/4 leads to the formation of DC1 cells and the secretion of IL-12, which directs the development of the adaptive response along the Th1 pathway.
The destruction process includes the following stages:
- Specific Th1 lymphocytes recognize epitopes on MHC-II of infected macrophages.
- The T cell delivers an activating signal to the macrophage via the interaction of the CD154 molecule (on the lymphocyte) and CD40 (on the macrophage).
- Th1 lymphocytes secrete a complex of cytokines, the main ones being IFNγ and TNFα.
- Under their action, the expression of inducible nitric oxide synthase is triggered in the macrophage.
- Nitric oxide (NO) is synthesized, which combines with the superoxide radical to form peroxynitrite—it is this factor that penetrates the phagosomes and causes the death of mycobacteria.
If an effective Th1 response does not develop (against the background of cellular immunodeficiency or a shift to Th2), the body walls off the infection by forming a granuloma. This is a manifestation of delayed-type hypersensitivity (DTH), which restrains bacteria but simultaneously leads to immune tissue damage. Meanwhile, the humoral response lacks protective significance, and immunological memory (after infection or BCG vaccination) remains low.
Briefly: answers to topical questions
What is the exact role and mechanisms of action of Th17 lymphocytes in defense against extracellular bacteria?
The role of Th17 lymphocytes is to recruit and activate neutrophils to implement immune effects. Their mechanism of action is based on the secretion of specific cytokines:
- Interleukin-17 (IL-17) is the dominant secreted product that acts on neutrophils and endothelial cells.
The development of Th17 cells and their production of interleukin-17 is stimulated by the cytokine IL-23, which, together with IL-17, maintains neutrophil homeostasis. At the same time, hyper-reactivity of Th17 lymphocytes often turns into pathology, as they play a leading role in the development of autoimmune processes and damaging forms of inflammatory reactions.
What types of cells are included in the histological composition of a tuberculous granuloma in delayed-type hypersensitivity?
The histological composition of a tuberculous granuloma includes cells of the monocytic-macrophage series and lymphocytes. According to the sources, the formation process includes:
- Monocytic phagocytes — accumulate in the lesion focus.
- Macrophages — formed upon the maturation of monocytic phagocytes.
- Epithelioid cells — formed during the transformation of macrophages and monocytic phagocytes.
- Pirogov–Langhans giant multinucleated cells — characteristic of giant-cell granuloma; have a peripheral arrangement of oval nuclei.
- Lymphocytes — are part of the cellular composition of the tuberculous granuloma.
In the center of the epithelioid-cell and/or giant-cell tuberculous granuloma, caseous necrosis is formed, containing remnants of dead macrophages, Mtb, and elements of the destroyed tissue of the affected organ.
To memorize the activation sequence in intracellular infection: A dendritic cell secretes IL-12, which induces Th1, and the latter fires a "doublet" of IFNγ + TNFα to turn on NO synthase and kill the pathogen.
Class and exam questions
Why are follicular dendritic cells needed?
In germinal centers, they retain immune complexes on their surface, ensuring the selection of B-lymphocyte clones with the highest affinity for the antigen.
Why can't a macrophage digest Mycobacterium tuberculosis?
The bacterium causes incomplete phagocytosis: it disrupts the fusion of the phagosome with the lysosome (no EEA1 factor) and blocks V-ATPase, preventing an acidic environment from being created inside the phagosome (pH remains around 6.0–6.3).
What molecular factor directly kills mycobacteria inside the macrophage?
Bacterial death is caused by peroxynitrite—a toxic compound formed by the interaction of nitric oxide (NO) with the superoxide radical under the influence of the cytokines IFNγ and TNFα.
What else to study on this topic
- Processes in germinal centers: isotype switching and hypermutations.
- Interaction of co-stimulatory molecules (CD40-CD154) in lymph nodes and tissues.
- Mechanisms of formation and structural features of the granuloma.
- The role of γδ T lymphocytes in the early immune response.
- Pathogenesis of immune damage via the delayed-type hypersensitivity (DTH) mechanism.
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Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"
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