Mitogens and microbial complement activation

Mitogenic effect of microorganisms

A number of pathogens carry molecules on their surface that exert a pronounced mitogenic effect on B lymphocytes. In low doses, such substances behave as type 1 thymus-independent antigens (TI-1 antigens), whereas at high concentrations they trigger a massive mitogenic response.

This reaction is highly disadvantageous for the host organism. It leads to colossal and wasteful expenditures of plastic material and energy. A vast number of B cells are recruited into the process, yet no protective effect is achieved. Primarily IgM antibodies with very low antigen affinity are synthesized, and immunological memory is completely absent.

Combined-action molecules: LPS example

Certain pathogen structures simultaneously combine the properties of pathogen-associated molecular patterns (PAMPs), antigens, and mitogens. A classic example is lipopolysaccharide (LPS).

LPS interacts with the TLR-4/CD14 receptor complex. This leads to the activation of innate immune cells and antigen-presenting cells (APCs) with the expression of co-stimulatory molecules, which normally should aid the adaptive immune response. However, the effect of LPS is strictly dose-dependent:

• In low doses: acts as a T-independent antigen. It is recognized by B-cell receptors (BCR) and triggers a specific, albeit low-yield, humoral response.
• At high doses: exhibits mitogenic properties that hinder the normal development of humoral defense.

Neutralization of antibodies and complement

Microorganisms are capable of directly binding key humoral factors, stripping them of their activity.

Interaction with immunoglobulins Bacteria synthesize proteins that act as false Fc receptors. For instance, protein A in the cell wall of Staphylococcus aureus (especially abundant in the Cowan strain) specifically binds to the C_H2 and C_H3 domain regions of immunoglobulins G (IgG). It competes with the true Fcγ receptors of host phagocytes, leading to a sharp decrease in bacterial opsonization. Bacterial protein G exhibits a similar competitive effect.

Binding of complement components Viruses interfere with the complement system, primarily disrupting its classical activation pathway:

• Herpes simplex virus binds the C3b component.
• Vaccinia virus intercepts the C4b component.

Cytokine manipulation

Viruses actively produce factors that modify the immune response through direct cytokine binding or mimicking their effects.

1. Shope fibroma virus secretes a soluble factor that captures tumor necrosis factor (TNFα). This prevents the cytokine from binding to cell receptors and blocks the development of inflammation.
2. Vaccinia virus synthesizes the serine protease inhibitor ICA. In a healthy organism, this enzyme is critical for apoptosis and the formation of mature interleukin IL-1β.
3. Epstein–Barr virus (EBV) expresses the DCRF1 gene product, a protein homologous to human IL-10. It fully replicates its immunosuppressive properties: it suppresses pro-inflammatory cytokine secretion and halts the differentiation of Th1 cells. As a result, the immune response shifts toward a less effective humoral pathway to the detriment of cell-mediated immunity, which plays the primary role in fighting viruses.

Blockade of phagocytosis and antigen presentation

To protect against capture by phagocytes, microbes use components of their capsules (hyaluronic acid in Gram-positive bacteria, fimbriae in streptococci, spike proteins in neisseriae).

Mycobacterium acts in a more complex way: it expresses a protein that binds fibronectin. The latter acts as an opsonin for macrophage β1-integrins and helps the bacterium penetrate inside. Once inside, the mycobacterium secretes factors that prevent phagosome-lysosome fusion. As a result, it hides intracellularly and multiplies. It can only be killed by IFNγ, which stimulates the production of nitric oxide (NO) in the phagocyte.

MHC suppression and NK cell evasion Viruses massively downregulate the expression of major histocompatibility complex (MHC) molecules to impair the presentation of their antigens:

• Adenoviruses block MHC-I (CD8+ lymphocytes are suppressed).
• Measles virus downregulates MHC-II (CD4+ lymphocytes are suppressed).
• Cytomegalovirus (CMV) suppresses molecules of both classes.

Downregulation of MHC-I should activate natural killer cells (NK cells). To avoid this, CMV enhances the expression of a molecule similar to non-polymorphic HLA-E, which inhibits NK cells. Viruses can also interfere with killer cell activation via stress proteins: for instance, the cytomegalovirus protein UL16 binds MIC and ULBP molecules, preventing them from fulfilling their protective function.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanisms of suppressing the uptake and processing of glycolipids by viruses (the role of CD1d molecules).
• Features of innate immune cell activation via the TLR-4/CD14 complex.
• The role of the serine protease ICA in generating the active form of IL-1β and triggering apoptosis.
• The protective activity of stress proteins MIC and ULBP during the recognition of infected cells.
• The structure and functions of bacterial capsules (neisserial spike proteins, streptococcal fimbriae) as phagocytosis inhibitors.

Other topics in the section "Immunity in defense and damage of the organism. Pathology of immunity"

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