Team:Slovenia/Background/Immune response

Immunity is a state of sufficient biological defenses to avoid infection, disease or other unwanted biological invasion. It is divided in a non-specific (innate) and specific (adaptive) components. The term innate immunity is due to its constant presency in healthy individuals and generally refers to responses that do not require previous exposures to the pathogen, whereas adaptive immunity develops more slowly and is specific to a particular pathogen and involves immunological memory. The adaptive immunity consists of humoral immunity in which antibodies neutralize and eradicate extracellular microbes and toxins and cell-mediated immunity in which T-lymphocytes play a key role. The most important is the cooperation between innate and adaptive immunity.

Until recently innate immunity was largely ignored as the adaptive immunity was thought to play a key role in the immune response. Now it became clear that innate immunity has an important role as the first line of defense against pathogens as well as in development of an adaptive immune response. The polarization of immune response largely depends on the initial signals that are brought by innate immunity. There are some essential signals, required to induce T- and B-cell responses. Innate immune signals modulate the quantity and the quality of adaptive immune response and are required to initiate an effective immune response, that mainly depends on the nature of the pathogen. There are two separated ways of antigen processing, which enable the immune system to appropriately respond against extracellular and intracellular pathogens, respectively.

Briefly, we will focus on the immune response against extracellular pathogens. As the pathogen invades the host, its pathogen associated molecular pattern (PAMP) is being recognised by the pathogen recognition receptor (PRR) on APC, for instance dendritic cell (signal 1 in immune activation). Pathogen recognition and APC activation is the first signal needed for activation of immune response. After internalisation (phagocytosis) antigens are processed into peptides. These antigen-derived peptides are presented by major histocompatibility complex (MHC) class 2 molecules on APC surface for recognition by CD4+T lymphocytes that have T-cell receptor specific for the same peptides. TCR recognition of specific peptide represents signal 2 in immune activation. The last step - signal 3 in immune activation is co-stimulation, which depends on the interactions between costimulatory molecules, such as B7 and CD40 on APC and CD-28 and CD40L on CD4+T. All this is happening at the first stages of immune response and leads to the expression of appropriate immune mediators, such as cytokines, that enable the polarization of immune response in a direction, that is potentially optimal for pathogen eradication.

For example, when IL-12 is absent or set of interleukins like IL-4 and IL-10 are present, T-helper 2 cell polarization occurs. T-helper 2 cells produce interleukin IL-4, IL-5, IL-6, IL-10, IL-13 and participate in phagocytosis-independent responses. They provide B-cell help and the induction of IgG1, IgE and IgA, which all provide the defense against extracellular pathogens. For instance, IL-4, that is produced by T-helper 2 cells, promotes IgE heavy chain class switching. These antibodies are effective against helminths, since IgE has Fc, which is recognized by Fc-ξRI on eosinophills, that finally eradicate the parasitic infection.

So it is obvious, that interactions between Th and B-cells is of a great importance. B-cells are a special type of APC's that are a part of adaptive immune response. In contrast to macrophages and dendritic cells, which have extracellulary exposed PAMP's, B-cells retain specific B cell receptors (BCR) that are basically membrane-bound immunoglobulins, which bind a particular antigen. After B cell encounters and recognizes a fitting (cognate) native antigen with its B-cell receptor, internalization, antigen processing and presentation of antigen derived peptides in MHC class II molecules occurs (for B cell is APC). This leads to the interaction with previously activated T-helper cell that carries T-cell receptor, specific for the same antigenic component, that is presented in MHC class 2 molecules of B cell. Only after this specific interaction B-cell receives an additional signals from a T-helper cell which leads to a clonal expansion and differentiation of a B-cell that carries an appropriate BCR. The net result is a production of antibodies of the same specifity and later on, also affinity maturation and heavy chain class switching, which all is necessary for effective humoral response. The final stage is an establishment of a memory B-cell repertoire, that quickly responds to a subsequent exposition to the cognate antigen.

In contrary, defense against intracellular pathogens is carried out by different strategy since humoral response is not effective against intracellular patogens, such as viruses and intracellular bacteria In that case, cytosolic antigens are presented within MHC class 1 molecules, which can be found on all nucleated cells, for all these cells could be infected by viruses. Antigenic peptides, presented in MHC class 1 molecules, are recognised by CD8+T cells, which then, with help of Th cells differentiate into CTL. These kill infected cells and eradicate infection.

This demarcation in antigen processing pathways ensures that CD4+ T cells target exogenous antigens to provide help to B cells. B cells internalize antigens through their B cell receptor and help CD8+ T cells to recognize their cognate ligand co-presented by DCs. This demarcation also ensures that CD8+ T cells target endogenously synthesized antigens in infected cells for selective recognition and killing. DCs can also internalize exogenous antigens and present them within MHC class 1 molecules in a process called cross-presentation.

Following internalization, DCs migrate to lymph nodes delivering information from microbial pathogens and infected cells in the periphery to naive T cells, which lead to subsequent orchestration of immune response.

Very simplified, we can say, that the result (polarization) of immune response depends on which player of innate branch of immune response (e.g., dendritic cell) recognized invading pathogen, how the peptides were derived from antigenic component presented (MHC class I or II molecules) and which immunomodulatory molecules were produced (e.g., IL-12). Therefore, cooperation between initial innate and subsequent adaptive response is needed for effective functioning of the immune system and immune response.