Understanding the Human Immune System

Overview of the Immune System

• The immune system defends against harmful or foreign substances.
• A complex network of cells and proteins comprises it.
• Innate and adaptive immunity constitute the two levels of immunity.

Innate Immunity

• Innate immunity is non-specific and fast-acting.
• The primary line of protection against pathogen invasion is innate immunity.
• Natural killer cells, mast cells, granulocytes, macrophages, dendritic cells, and monocytes are involved.
• Macrophages, dendritic cells, and monocytes are phagocytic cells that use phagocytosis.
• Receptors on these cells recognize microbial products known as antigens.

Adaptive Immunity

• It is slower-acting, but more specific than innate immunity.
• Specialized systemic cells and processes make up adaptive immunity.
• Humoral and cellular components divide the immunity.

Humoral Immunity

• Humoral immunity is mediated by activated B cells.
• B cells produce and secrete antibodies against specific antigens.

Cellular Immunity

• Cellular immunity is mediated by T lymphocytes, also called T cells.
• T cells circulate throughout the body until a specific antigen is recognized.
• T cells recognize specific antigens on the surface of antigen-presenting cells (APCs) like dendritic cells.
• The T cell receptor (TCR) on both CD4+ helper T cells and CD8+ cytotoxic T cells binds to the antigen.
• The "major histocompatibility complex" (MHC) holds the antigen.
• The MHC discriminates foreign from self-antigens, initiating adaptive immune responses.
• A signaling cascade allows T-cells to replicate, differentiate and secrete signaling proteins called cytokines.
• Cytokines activate more cells of the immune system.
• CD8 or CD4 binds to the MHC molecule, depending on the type of T-cell.
• Signal transduction then occurs through CD3 associated with the T cell receptor.

T-Cell Activation

• The initial signal through CD3 is not sufficient for T-cell activation.
• A secondary signal, or costimulation, is required.
• Costimulation occurs when CD28 receptor on T cells binds CD80 and CD86 molecules on antigen-presenting cells (APCs).
• This triggers a calcium-mediated signaling cascade.
• A rise in intracellular calcium levels leads to activation of the phosphatase calcineurin.
• Calcineurin dephosphorylates nuclear factor of activated T-cells (NFAT).
• NFAT translocates from the cytoplasm into the nucleus.
• NFAT proteins bind DNA target sequences with partnering transcription factors (TF) inside the nucleus .
• This leads to activation of genes encoding cytokines, including interleukin 2 (IL-2).
• Generated IL-2 binds to the IL-2 receptors on the surface of T cells.
• This activates the mammalian target of rapamycin (mTOR).
• mTOR allows the cell to progress through the cell cycle, promoting cell proliferation of antigen-primed T cells.
• These cells produce more IL-2, and other pro-inflammatory cytokines.
• Natural killer cells, macrophages, and cytotoxic T cells are thus activated.

Immunosuppressants Overview

• The immune system is critical to survival, but can lead to chronic inflammatory diseases such as autoimmunity or cancer.
• It serves as a barrier for the transplantation of certain beneficial organs and tissues.
• Continuous use of immunosuppressive drugs is standard for managing autoimmunity and transplant rejection.
• Immunosuppressive drug therapy usually consists of two or more agents with different mechanisms of action.
• These agents disrupt various levels of T-cell activation.

Calcineurin Inhibitors

• Drugs in this group bind to intracellular proteins called immunophilins.
• Immunophilins consist of two protein families: cyclophilins and FK-binding proteins.
• Cyclosporin and Tacrolimus are the major drugs in this group.
• Cyclosporin binds to cyclophilins.
• Tacrolimus binds to FK-binding proteins.
• These complexes bind to and inhibit calcineurin.
• This prevents nuclear factor of activated T cells (NFAT) from moving to the nucleus.
• This impairs transcription of the genes encoding interleukin-2 (IL-2) necessary for activation of T cells.

Costimulation Blockers

• Belatacept and Abatacept belong to this group.
• They selectively bind to CD80 and CD86 on antigen-presenting cells (APC).
• This blocks interaction with CD28 on T cells.
• This prevents complete T-cell activation, reduces T-cell proliferation and IL-2 production.
• Belatacept was designed to bind to CD80 and CD86 more strongly than Abatacept.
• Belatacept is more effective in the immunosuppression necessary for transplant rejection.

mTOR Inhibitors

• Sirolimus (Rapamycin) and Everolimus are drugs in this group.
• They bind to the same intracellular FK-binding protein as Tacrolimus.
• Instead of forming a complex with calcineurin, they bind to mTOR thereby inhibiting its activity.
• This leads to slowing or arrest of cell cycle progression.
• This also leads to inhibition of the cellular response to IL-2.

Immunosuppressive Antimetabolites

• Azathioprine and Mycophenolate mofetil are commonly used agents in this class.
• Azathioprine is first activated to become 6-mercaptopurine (6-MP).
• 6-MP is further metabolized to form purine analogs that mimic the structure of a building block of DNA.
• These false purines can disrupt de novo pathway of purine synthesis.
• The false purines can become incorporated into DNA and RNA terminating their synthesis ultimately inhibiting cellular proliferation.
• Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase (IMPDH).
• IMPDH is a key enzyme in purine synthesis, involved in guanosine nucleotides.
• As a result, DNA synthesis, which requires guanosine triphosphate (GTP), does not occur and cell proliferation is inhibited.
• Mycophenolate is not incorporated into DNA and does not induce chromosome breaks, unlike Azathioprine.

Corticosteroids

• Often used for immunosuppression in both transplantation and various autoimmune disorders.
• Prednisone, Prednisolone and Methylprednisolone are drugs in this class.
• Effects are diverse and are likely controlled by several mechanisms.
• Corticosteroids induce immunosuppression through regulation of the T-cell responses.
• Corticosteroids mediate their effects by binding to the intracellular glucocorticoid receptor (GR) directly on T cells.
• This results in translocation of the complex to the nucleus and subsequent inhibition of key transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1).
• This alters gene transcription and represses pro-inflammatory genes.
• Corticosteroids exert non-genomic actions by causing rapid dissociation of a T-cell-receptor-associated protein complexes.
• This results in impaired receptor signaling and T-cell activation.

Antibodies

• Many different antibody products exist, but this lecture focuses on the two that are most commonly used to prevent transplant rejection.
• Antithymocyte globulins consist of polyclonal antibodies that bind to a wide variety of proteins on the surface of T-cells.
• This leads to cell death via complement mediated cytotoxicity or apoptosis.
• Basiliximab is a monoclonal antibody that binds to IL-2 receptor with similar affinity as IL-2.
• Basiliximab effectively competes with IL-2 and subsequently inhibits IL-2 driven T-cell proliferation.