Adaptive Immunity Proteins

 Adaptive Immunity Proteins Background

Although innate immunity is critical for survival, over time pathogens have evolved mechanisms to evade and overcome innate immunity. It was under this selective pressure that an adaptive immune system evolved in vertebrates. The adaptive immune system first emerged in early fish and consists of lymphocytes and their products, which likely evolved from the more ancient innate immune system. As its name suggests, adaptive immunity is not preexistent to an encounter with a specific pathogen as is innate immunity. Instead, adaptive immunity develops with specificity for a pathogen when the body encounters that particular pathogen for the first time. Adaptive immunity is further distinguished from innate immunity because of a unique property: memory. That is, upon subsequent infection with the same pathogen, the adaptive immune system remembers the pathogen and mounts a faster and stronger response to eliminate the pathogen from the body. However, the adaptive immune system does not operate alone, but works in coordination with the innate immune system. The role of antibodies as opsonins directing phagocytosis has already been mentioned. Conversely, innate immune cells play roles in activating the adaptive immune system.
The cells of adaptive immunity are B and T lymphocytes. Lymphocytes make up 20-40% of the human leukocyte population and also include natural killer cells. B lymphocytes, or B cells, mature in the bone marrow. T lymphocytes, or T cells, mature in the thymus. B cells are responsible for the production of antibodies, which are the major effector molecules of humoral immunity. On the basis of their function in the immune response, T cells are divided into two categories: T helper (TH) lymphocytes and cytotoxic T lymphocytes (CTLs). TH cells orchestrate the activity of other cells of the immune system by releasing messenger molecules known as cytokines and are subdivided into T helper type 1 (TH1) and T helper type 2 (TH2) cells on the basis of the cytokines they produce. TH1 cytokines preferentially direct immune responses against pathogens that invade cells and against tumors, whereas TH2 cytokines preferentially direct immune responses against extracellular pathogens. CTLs eliminate target cells, such as tumor cells or cells infected by viruses, by producing molecules that form pores on their surface. CTLs then use the pores on the target to insert additional molecules that specifically induce cell death. 
The keystones to adaptive immunity are receptors that recognize parts of the pathogens referred to as antigens. These receptors are of two different types that are known as B cell receptors (BCR) and T cell receptors (TCR) for the respective lymphocytes on which they are found. BCRs are composed of membrane bound immunoglobulin molecules and ancillary signaling proteins. In contrast to receptors of innate immunity, BCR and TCR expression involves reorganization of the genes encoding them. This reorganization occurs in the lymphocyte progenitor cells, found in the bone marrow for B cells and in the thymus for T cells, and involves stochastic shuffling of gene segments and insertion of nucleotides to create receptors with unique antigen specificity that are exclusive to each differentiated lymphocyte and its daughter cells. Each clone produced in this manner undergoes negative selection whereby clones with antigen receptors that recognize self-proteins are induced to undergo apoptosis or to enter a state of inactivation known as anergy. Unfortunately, this process is imperfect and can lead to autoimmune disorders in which the body attacks itself. Hence, autoimmunity is a byproduct of a dysfunctional adaptive immune system. TCRs only recognize processed antigen presented by major histocompatibility molecules (MHC) expressed on the surface of cells, in contrast to BCRs that recognize unprocessed antigen directly. Therefore, T cells also undergo positive selection. The process of positive selection allows only development of T cells bearing TCRs that recognize MHC molecules. All other T cells undergo apoptosis.
Newly formed B cells and T cells are naïve and must first be activated prior to performing the immune effector functions that ultimately eliminate pathogens. B cell activation generally requires two signals. The first signal is provided when antigen is recognized by the BCR. The second signal comes from the cognate interaction with a T cell. The antigen bound to the BCR is internalized, processed, and presented as a peptide on MHC class II molecules to a T helper cell. T helper cells that recognize the antigen through their TCR become activated and provide costimulatory signals and cytokines that complete the activation process of B cells. Some antigens provide a strong enough signal to activate B cells in the absence of T cells. These antigens are known at T cell independent antigens, an example of which is vesicular stomatitis virus that has multiple identical antigen binding sites, or epitopes. By having these epitopes located in close proximity to each other, several BCRs are brought together by binding a single virion at once. This cross-linking of the BCR then leads to an intracellular signaling cascade that activates the B cell. Once activated, B cells proliferate and differentiate into effector memory cells and antibody secreting plasma cells. As mentioned, antigen presented in the context of MHC class II molecules can activate T helper cells. For this reason, B cells along with macrophages and dendritic cells that also bear MHC class II molecules are known as professional antigen presenting cells (APC). CTL like T helper cells must be presented with antigen in the context of MHC molecules, but CTL recognize antigen presented by MHC class I molecules, which present endogenous antigens and are expressed on virtually all cell types (the only exception is represented by red blood cells). CTLs activated through recognition of MHC class I presented antigen kill the presenting cell. Adaptive immune responses are classified as humoral or cellular based on whether the response to clear antigen involves antibodies, or cellular mechanisms, such as those used by CTL.

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