A hypersensitivity reaction is an overreaction to a foreign antigen which then causes serious damage to the body’s tissues. There are four types of hypersensitivity reactions: type I is immunoglobulin E, or IgE mediated; type II is mediated by antibodies that activate cellular cytotoxicity, type III is mediated by immune-complexes, and type IV is a delayed T cell-mediated hypersensitivity reaction. A type III hypersensitivity reaction occurs when antibodies attach to soluble antigens and form antibody-antigen complexes that float around the blood vessel, causing tissue damage depending on where they end up.
Let’s start by discussing the physiology of the humoral immune response. The humoral immune response is the part of the immune system that provides protection against invading pathogens by utilizing antibodies designed to specifically target certain antigens. It all begins in the bone marrow, where undifferentiated hematopoietic stem cells differentiate into various types of white blood cells, including and T lymphocytes, or B and T cells, for short.
When a pathogen, like a bacteria or virus enters the body, it runs into antigen-presenting cells, or APCs. APCs like macrophages or dendritic cells, then engulf and digest the pathogen, and the fragments are then presented on the APC’s surface via proteins called major histocompatibility complex class II, or MHC II. Now these fragments serve as antigens that can trigger an immune response. So the APCs present these antigens to T helper cells which have T-cell receptors, or TCRs, that recognize the antigen.
These T helper cells go on to activate specific B cells which causes them to transform into plasma cells that could produce antibodies against the specific antigen.
Antibodies called IgM and IgG are produced and they can attach to the antigens on the bacteria or virus, creating an antigen-antibody complex. Next, the complement system activates, which is a group of different proteins named C1 through C9 created by the liver and released into the blood. When these complement proteins encounter an antigen-antibody complex, they activate the complement cascade where one complement protein helps activate the next one in sequence by helping enzymes cleave them to functional fragments.
So first, C1 attaches to the antigen-antibody complex that forms on the bacteria and activates other complement proteins.
Some of these complement proteins attract macrophages and neutrophils to the area where they release enzymes that create oxygen free radicals that’s harmful to the bacteria. Others can attach to the pathogen and mark it as a target for the macrophages to phagocytose. The rest form membrane attack complexes, or MAC, on the bacteria’s surface which then creates a hole that lets surrounding fluid leak into the cell and intracellular content leak out, causing the cell to die.
Now, to ensure the immune cells do not attack their owner’s tissue, there are processes called central and peripheral tolerance. Central tolerance causes immature T cells in the thymus and B cells in the bone marrow to self-destruct if they react to any self antigens. In peripheral tolerance, surviving T and B cells are tested again after they leave the thymus and bone marrow and any self reactive immune cells that were missed by central tolerance are destroyed.
Now, type III hypersensitivity reactions can be caused by exposure to soluble antigens, meaning antigens that are not bound to the cell surface. These antigens can be exogenous or foreign; and endogenous or self-antigens.
Important risk factors associated with type III hypersensitivity reactions include positive family history; genetic predisposition; infections, like hepatitis B; antiserum, antivenom; as well as the use of some medications, such as penicillins and cephalosporins.