Immunology

Inflammation & the 

Type IV Cell-Mediated Immune Response

From the book, Immunology Notes
 by Stephen Gislason MD

Introduction to Immunity

Immune Networks

Antibodies

Immune Cells

Food Allergy

Allergy Center

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Inflammation is one of the most common mechanism of disease. In medical terminology the suffix "itis" refers to inflammation. When you consider that the majority of diseases have names ending in "itis" you have to be interested in inflammation, its causes and cures.  Inflammation is manifest by  pain, swelling, redness band loss of function in the afflicted tissue. The process is created by immune cells invading the tissue like an army in full battle mode. 

Chronic inflammation is a product of the Type IV hypersensitivity mechanisms. Cell-mediated immunity is initiated by several cell populations, including mast cells, macrophages, eosinophils, and neutrophils. The net effect of sustained immune activity in any target organ is inflammation with local dysfunction, associated with systemic symptoms from immune mediators released into the bloodstream. Immune activity in GIT, for example, may create systemic symptoms by mediator release.

Cell populations in chronic inflammation can be diverse and in specific diseases may assume features which distinguish one inflammatory process from another. You can usually count on a swarm of lymphocytes infiltrating the inflamed tissue. If a macrophage-lymphocytic network is activated by food antigens the pathogenic consequences depend on the dose, frequency, and distribution of antigen, and the location of lymphocytes. The idea is that any part of the body can be involved in an immune skirmish. The consequences depend on the importance of the target organ the nature and extent of problems caused by immune activity. Events in the nose will be experienced as discomfort. Events in the eye or other critical areas of the brain may be catastrophic.

Inflammation is often triggered  by circulating immune complexes that enter tissues. Immune complexes are found in rheumatoid arthritis in joints and as CICs in patients with systemic disease. Joint destruction begins as a vasculitis with increased capillary permeability, edema, followed by cell infiltrates that create and maintain inflammation. A constant supply of antigen is available from the food supply to maintain chronic inflammation and therefore is important to consider food causes of inflammation as in asthma, arthritis and other "autoimmune diseases".

The Arthus mechanism begins as a vasculitis initiated by circulating immune complexes entering the tissue through blood vessel walls. Although vasculitis is commonly associated with hypersensitivity reactions to drugs or infections, unexplained cases may be due to food antigens. A leukocytoclastic vasculitis such as Henoch-Schonlein purpura can be associated with food allergy and urticaria. A purpuric rash develops over the lower extremities, buttocks and forearms. Joints and kidneys may be involved. The lesions of urticarial vasculitis tend to be flatter erythematous patches that hurt rather than itch and last longer than the more typical itchy wheals. Chronic inflammatory infiltrates are found around venules with deposits of immunoglobulins and complement. CICs may adhere to endothelium and trigger inflammation in blood vessel walls. In Bechet's disease, an occlusive vasculitis, the basement membrane of the vessel is under attack resulting in small vessel infarction with perivascular infiltration of lymphocytes.

Because of evidence that cow's milk intake can trigger diabetes in rodents, a study of diabetic children showed that antibodies to bovine serum albumin and a 17-amino-acid bovine serum albumin peptide (ABBOS). These antibodies would bind to a pancreatic beta-cell surface antigen. This study showed that diabetic patients had high serum concentrations of anti-BSA antibodies (IgA and IgG). The presence of antibody ( which means presence of antigen-specific B-cells) may signal the concomitant presence of antigen-specific cytotoxic T-lymphocytes, although these have not yet be demonstrated. The researchers suggest that ... "relevant clones ( of lymphocytes) are continuously transferred from immature IgM-expressing B-cell compartments to pools of IgG-secreting or IgA secreting cells" They go on to describe "... a slow inefficient process, consistent with the fact that clinical disease develops in only about 5 to 6 % of hosts with the relevant genetic predisposition."

The diabetes model of food-antigen triggered disease is a potentially important immunological model of many unsolved diseases which appear to be "autoimmune". Autimmune-immune probably means that the antigenic source is not recognized and that a long-term, inefficient pathogenesis produces slow or intermittent target-organ damage, especially if the antigen challenge continues over many years. Alternative explanations suggest that beta cells are attacked by cytotoxic T-cells after they are infected by a virus, or by T-cells originally targeted on other cells infected by virus whose cell-surface antigens happen to resemble beta cell antigens. An Australian study of children who developed diabetes found that children given cows milk formula in the first three months were 52% more likely to develop diabetes than those not fed milk. Breast fed infants had a 34% lower incidence of diabetes than formula fed infants. An Italian study showed that exposure to beta casein produced proliferation of T- lymphocytes from the blood of 51% of 41 insulin dependent diabetics.

The response of blood lymphocytes to hens egg albumin was studied in patients with atopic dermatitis and asthma. In a detailed and complicated analysis of T-cell sub-populations they showed that antigen stimulation activated (induced IL-2 responsiveness) a group of helper t-cells (CD3+2+4+8-45RA+) which function as generators of the delayed-type hypersensitivity reactions. When food antigens get into the body - either free-form or in complexes - there are going to be complicated reactions going on. The expansion of activated lymphocytic clones and the secretion of cytokines are two of the contingencies that patients with food allergy must contend with.

Exogenous antigens make their way through human bodies in a remarkable fashion. Consider the long and improbable path of milk proteins through a mother's gut, into her blood, through her liver, out into her breast milk, through her infant's gut mucosa and into the infant's nasal mucosa to cause rhinitis, the lung to cause asthma, or the skin to cause eczema. There are many potential paths from mouth to target organ for food antigens to follow.  Some activity is noticed in minutes; the onset of other activity is delayed hours to days. Manifestations include both systemic symptoms such as flushing, fever, aching, fatigue, and also localized target organ activity, usually some form of inflammation, manifest as pain, swelling, erythema, and local heat.

Antigens may enter and then complex with antibody in the GIT wall causing local inflammation and increased permeability. Immune complexes may form in the gut submucosa and pass through lymphatics or capillaries in the general circulation. Free antigen may enter the circulation and be identified by circulating antibodies forming circulating immune complexes (CICs). CICs in the portal circulation pass to the liver where they may be cleared by macrophages. However, if the immune complexes are passed beyond the liver, they will then circulate through the lungs which act as secondary filters and may suffer CIC-triggered inflammatory events. An asthmatic with immediate hypersensitivity typically experiences an acute wheezing attack within minutes of exposure to an airborne of allergen. This initial attack is followed by remission for a few hours, but then dyspnea returns. The second or late phase is associated with bronchiolar inflammation, airway obstruction, not responsive to bronchodilators and a more prolonged and serious threat to respiration ensues. The variable delay of absorption of food antigens and the biphasic asthma response to discrete antigen challenge makes for a confusing variability in the timing of symptom-sequences following food ingestion. Further confusion arises when antigen challenge comes from food eaten everyday and acute responses overly chronic inflammatory activity in a complex and variable system of symptom production.

In ulcerative colitis and Crohn's disease, antigen enters through gut mucosa and binds to the basement membrane of the uvea and episcleral vessels triggering anterior uveitis and episcleritis. "In ulcerative colitis... the membrane bound antigen may be attacked by antibody and cytotoxic lymphocytes, leading to complement pathway activation and associated acute inflammatory cell infiltrate."

In SLE, retinal vasculitis produces cotton wool spots, retinal hemorrhages, retinal and optic nerve edema. The cotton wool spots are thought to represent sites of infarction in the nerve fiber layer when deposition of CICs has taken place in the capillaries.