Immunopathology

   Here we shall be looking at three main categories of immune failure:

                               Immunodeficiency, autoimmunity, and hypersensitivity.

In a healthy person with a normal immune response, pathogens are identified as being foreign, and are destroyed by appropriate immune effector mechanisms.

    However, in an immunodeficient individual, this immune response is impaired or non-existent, making them prey to opportunistic infections such as candidiasis of the mouth. This absence of an immune response allows the infection to spread uncontrollably.

    In an individual, with autoimmune disease, the immune system fails to tolerate its own tissue and makes an immune response against it.

Typical autoimmune diseases include rheumatoid arthritis and ulcerative colitis. Here we see this effect in pemphigoid, an autoimmune reaction against components of the skin.

The pictures show the histological appearance of a sub-epidermal blister, and auto-antibodies demonstrated by immunoflorescence on the basement membrane of mucosal epithelium.

    The third category of immune failure is hypersensitivity, an adaptive immune response which occurs in an exaggerated or inappropriate form.

There are four distinct types of hypersensitivity. The first three are antibody mediated, whereas the fourth is mediated primarily by T-cells and macrophages.

Type 1 hypersensitivity is characterised by an allergic reaction that occurs immediately following contact with the antigen, referred to in this case as the allergen. An example of this would be hay fever, where the allergen is pollen.

We can see how this allergy occurs if we look more closely at what happens when pollen is inhaled into the nasal tissue.

    Here we see a mast cell situated in the nasal tissue containing lots of granules containing mediators and with IgE antibodies bound to the Fc receptors on its surface.

Pollen antigen enters the body through the mucosal lining and cross-links these IgE antibodies.

This complexing leads to an influx of calcium ions into the mast cell causing it to degranulate and release vasoactive amines.

These then stimulate the mucosal lining causing the characteristic inflammation and increasing both vascular permeability and blood flow. Prostaglandins and leukotrienes are also produced, and these contribute to a delayed component of the reaction which often develops hours after the original exposure to the antigen.

   In the following types of hypersensitivity, types II and III, the mechanisms are illustrated in autoimmune disease. An example of type II hypersensitivity is Myasthenia gravis, an auto-immune disease which cause extreme muscle weakness.

   Here we see a nerve terminal situated above a neuromuscular junction. In a healthy person, a nerve impulse passes down the neurone, arrives at the nerve terminal and causes the release of acetylcholine.

This then diffuses across the neuromuscular junction and binds with specific receptors on the muscle fibre. This depolarises the muscle opening up ion channels in the muscle membrane, which then triggers normal muscular contraction.

In a person with Myasthenia gravis, auto antibodies are created which bind to the acetylcholine receptors blocking the signal and causing impaired neuromuscular transmission. Additionally, complement is activated and phagocytes migrate into the area and cause more damage.

    In type III hypersensitivity, an autoimmune response takes place against common antigens, such as DNA. Immune complexes form, and these become deposited, particularly in the kidney.

    Here we can see the fenestrated endothelium of the glomerulus, with its basement membrane through which filtration takes place.

Immune complexes circulating in the blood deposit on the endothelium. These complexes consisting of auto-antibodies bound to self-antigens, tend to deposit at sites of high pressure, filtration or turbulence, particularly the kidney.

Macrophages then attempt to phagocytose these complexes as they would bacteria. As these complexes are deposited on the basement membrane, the macrophages are unable to extend their pseudopodia around them. The macrophages then degranulate, releasing destructive lysozomal enzymes into the gap, damaging the basement membrane. This process is known as frustrated phagocytosis.

    Type four mechanisms give rise to what are known as delayed hypersensitivity reactions. Examples of these are contact dermatitis, caused by poison ivy, or in this case the nickel in the buckle of a watch strap.

    The nickel acts as a hapten, and it is absorbed into the skin, where it complexes with normal body protein molecules to form an antigen called a hapten-carrier complex.

These complexes then diffuse across the epidermis and get taken up by Langerhans cells expressing high levels of MHC class II molecules on their surface. These antigen presenting cells then present the hapten-carrier complex to T-cells in local lymph nodes. This produces a population of CD4 positive effector T-cells.

These activated T-cells migrate back into the epidermis, releasing cytokines and activating the local cells causing irritation. Some hours later, macrophages also migrate to the area of inflammation providing additional inflammatory mediators which attack the epidermis increasing the damage.