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Immune System & Autoimmune Disease

The human immune system is a complex network of special cells and organs that defends the body from germs and other foreign invaders. Its key tasks are to Detect infection or harm (Recognition), Contain and eliminate infection (Effector function), Control activity to avoid damage to the body (Regulation) and to remember exposure, react immediately and strongly upon re-exposure (Memory).

At the core of the immune system is the ability to tell the difference between self and non-self. Autoimmune diseases arise from an overactive and misguided immune response of the body against substances and tissues normally present in the body (self). In other words, the body makes autoantibodies, and actually attacks itself. At the same time special cells called regulatory T cells fail to do their job of keeping the immune system in line. The resulting damage is dependent on the type of autoimmune disease, for example in Crohn’s disease the body attacks the lining of the gastrointestinal tract. Overall, autoimmune diseases are common, affecting more than 23.5 million Americans. They are a leading cause of death and disability. Coronado Biosciences is currently focused on the following autoimmune diseases but many other autoimmune diseases may be amendable to treatment with TSO (Trichuris suis ova or CNDO-201).

The immune system has two broadly defined ways of behaving, Innate and Adaptive immunity, both required for normal function. The Innate system is present at all times, reacts immediately and generally, activates the adaptive system and does not improve with repeated exposure. The components within the innate system include macrophages, dendritic cells, myeloid cells (neutrophils, mast cells, basophils, eosinophils) NK cells, complement factors and cytokines. The Adaptive system develops in response to infection, is protective against specific pathogens, leverages components of the innate response and develops memory. The components within the adaptive system include T and B lymphocytes, antibodies and cytokines.

T and B cells are both lymphocytes but have very different functions. B cells are produced in the bone marrow, and are the precursors of T cells, which eventually mature in the thymus. Each B cell and T cell is specific for a particular antigen, meaning each is able to bind to a particular molecular structure. When the B cells, through their B cell receptors (BCR), bind to their antigens, they undergo a series of changes with the help of T helper cells, and develop into plasma cells that secrete antibodies, specific to the antigen. T cells also bind through their receptors (TCR), but they bind directly to an Antigen Presenting Cell (APC), which exposes the antigen in a bimolecular complex consisting of a major histocompatibility (MHC) molecule. There are two major types of T cells, determined by which kind of MHC complex is associated with the cell. CD8+ cells are the most well understood cells, and are also called cytotoxic T lymphocytes (CTL). They secrete molecules that destroy the cell to which they have bound. CD8+ T cells bind epitopes that are part of MHC class I, which are displayed on almost all cells in the body. CD4+ T cells bind an epitope consisting of an antigen fragment lying in the groove of an MHC class II, and are essential for both the cell-mediated and antibody-mediated branches of the immune system. For the former, the CD4+ cells bind to APC that start attracting other cells, which generate pro-inflammatory cytokines. For the latter, the CD4+ cells function as T helper cells, and aid the B cells in developing into plasma cells, which produce antibodies.

There are four kinds of T helper cells: Type 1 T helper (Th1) cells, Type 2 T helper cells (Th2) cells, T follicular helper (Tfh) cells and Type 17 T helper (Th17) cells. Th1 cells produce interferon-gamma, interleukin (IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity. By contrast, Th2 cells produce IL-4, IL-5, IL-10, and IL-13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions. Th1 cells mainly develop following infections by intracellular bacteria and some viruses, whereas Th2 cells predominate in response to infestations by gastrointestinal nematodes. Tfh cells also provide help to B cells enabling them to develop into antibody-secreting plasma cells. This occurs in nests of lymphoid cells — called follicles — in the lymph nodes. Th17 cells protect surfaces (e.g., skin, lining of the intestine) against extracellular bacteria.

10% of the CD4+ cells do not belong to any of the four kinds of T helper cell categories, but are called T regulatory cells (Tregs). These cells express a transcription factor called Foxp3 that alters the expression of many genes, a transmembrane protein called CD25 that is the alpha chain of the receptor for IL-2 and a cell-surface protein designated CTLA-4. When activated, they express large quantities of TGF beta and IL-10, two very strong immunosuppressants that inhibit the T helper cells, NK cells and CTLs. They also have a powerful, destructive effect on APCs like dendritic cells. IL-2 is secreted by Th1 cells, and amplifies the Tregs, providing a negative feedback mechanism for inflammation. The antigenic peptides recognized by the TCRs of Treg cells tend to be self-peptides and probably a major function of Treg cells is to inhibit other T cells from mounting an immune attack against self components; that is, to protect the body against autoimmunity.

In addition to playing different roles in protection, polarized Th1-type and Th2-type responses are also responsible for different types of immunopathological reactions. Th1 cells are involved in the pathogenesis of organ-specific autoimmune disorders, In contrast, allergen-specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals. The Th1/Th2 paradigm also provides the rationale for the development of new types of vaccines against infectious agents and of novel strategies for the therapy of allergic and autoimmune disorders. In people and animal models where there is a lack of Tregs (Foxp3 mutations or nude mice), horrible autoimmune conditions arise.