Immune Complexes - Type III Reactions
Immune complexes are formed when antibody binds to antigen. Circulating Immune Complexes (CIC) are formed in variety of circumstances and may trigger illness by a variety of mechanisms. The pathogenic significance of complexes depends on the antibody involved, the relative concentration of antibody and antigen, the distribution of complexes and the ability of the host to clear them. CIC play a pathogenic role variety of disease states including arthritis, polymyositis, vasculitis, glomerulonephritis, hemolytic anemia, leukopenia, and thrombocytopenia. They are found in infectious diseases, autoimmune diseases, following organ transplants, and in patients with food allergy.
Antibody excess tends to favor rapid clearing of complexes. Antigen excess favors complexes that stay longer in the circulation. Medium sized complexes tend to be more pathogenic and tend to get deposited in tissues. Tissue ICs can be identified by immunofluorescent staining of biopsy specimens. Serum IC measurements are neither easy nor reliable indicators of disease activity. Meaningful CIC measurement would have be carried out in a physiological manner - for example tracking in real time the serum and tissue concentrations of ICs following antigen challenge. Spot samples of serum CIC concentration will not yield very useful information.
Von Pirquet first described serum sickness, a prototype of immune complex disease. Any antigen entering the circulation in sufficient quantity can produce symptom patterns resembling serum sickness. The most direct model of food allergy involves free antigen entering the circulation and complexing with antibody to form circulating immune complexes (CICs). Immune complexes may form in the gut submucosa and be transported by lymphatic channels to regional nodes and may continue through to the thoracic duct to enter the systemic circulation.
Serum sickness evolves over a period of 7-10 days after a discrete antigen challenge. Manifestations include general malaise, fever, flushing, sweating, hives, swelling, bruising, arthralgias and myalgias, progressing in the worst case to inflammatory disease in target organs with protein in the urine from glomerulonephritis. In animal models a large single intravenous dose of bovine milk protein will induce serum sickness with vasculitis and glomerulonephritis. Immune complexes are present from day 5 through 13. With chronic administration of milk protein, 4 groups of animals emerge with different pathophysiologies as a function of antibody affinity and size of immune complexes:
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 which 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 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.
CICs and Complement
Complement is a series of serum proteins that undergo progressive
transformation into active by-products, once activated. Complement was first
discovered as serum activity that lead to the lysis of bacteria ( without help
from immune cells). Activation occurs in two ways:
2. Alternative pathway: chemicals such as microbial cell-wall polysaccharides trigger the alternative pathway directly as do some drugs ( and undoubtedly polysaccharides and other chemicals found in food materials). Once activated the complement cascades through a series of changes, producing 5 major effects:
The complement system modulates and amplifies the biological effects of CIC's. Immune-complex activated C1q cleaves hundreds of C2s and C4s; to form fragments c2a and C4b which act as C3 convertase, cleaving thousands of C3 proteins producing C3a, C3b and C5b fragments which are anaphylatoxins - release vasoactive mediators from basophils and mast cells, and increase vascular permeability. At the same time, certain complement products are essential to clear CICs. Individuals with deficiencies of complement proteins C1, C2 and C4 are at greater risk of developing immune-complex disease. C3 deficient individuals suffer from recurrent infections rather than immune complex disease.
CIC's activate complement by the classic pathway - C1q binds to the Fc portion of the antibody and C3b is produced to combine with CICs. CIC's may not cause tissue injury unless vascular permeability is increased - allowing influx of CIC's and cells. If CIC's leave capillaries, they trigger inflammatory events in target tissues. A classic model of complex-induced pathology is the Arthus reaction, which appears 3-6 hours after antigen challenge and involves large insoluble (Type 3) complexes with complement (C3b) passing through vessel walls to excite inflammatory responses in target tissues. The Arthrus reaction can be prevented by depleting C3 with Cobra venom. Type III activity can activate type I activity in the gut of rats where mast cell antigens can be released by the action of anaphylatoxins produced by antigen-antibody complexes.
Type IV Cell-Mediated Immune Response
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.
Systemic Lupus Prototype of Type III -IV Illness
Systemic Lupus Erythematosis (SLE) is an immune-mediated disease which serves as a model of hypersensitivity disease. The peak incidence of SLE is in women between the ages of 20 and 40 and who present with a typical malar rash, lymphadenopathy, arthralgias, fever, fatigue and will often complain of recurrent flu-like illness. As the disease advances, increased evidence of target organ damage can be found with protein and red cells in the urine, raised ESR, pleurisy, pericarditis, hair loss, associated with the appearance of circulating auto-antibodies, especially antinuclear.
SLE features circulating immune complexes and fits the model of delayed pattern food allergy (Type III and IV hypersensivity mechanisms). Patients with type III pattern food allergy (see chapter 5 for clinical examples) have lupus-like symptoms and signs for years, but only a small subgroup crosses over or decompensates into the more severe illness, SLE. The butterfly rash is common and is associated with cervical node enlargement. Arthralgias are associated with generalized aching and stiffness and infrequently joint swelling occurs. The type III patterns appears to be a milder manifestation of SLE and may not progress over many years. These patients do not have elevated ESR, and only occasionally have ANA titers above 1: 40. Some complain of recurrent chest pain which suggests pericarditis or pleurisy, but objective evidence is usually lacking.
A number of prescription drugs and several industrial chemicals are known to trigger auto-immune disease. Hydralazine, isoniazid, penicillamine, practolol and other drugs can induce SLE. While they may act as incomplete antigens and contribute to immune complex formation, the toxic effects of certain drugs on the complement system may also interfere with immune complex clearing and induce SLE indirectly. SLE can be considered a disease of immune complex handling - immune complexes containing non-cellular antigens are inappropriately deposited in tissues which are then damaged by inflammatory responses. A general thesis would suggest that drugs and chemical in the environment which promote the formation of immune complexes or impair the clearing of complexes would tend to induce autoimmune disease. Hydralazine, marketed as an anti-hypertensive drug, also occurs naturally in tobacco, smoke, mushrooms and may enter the food supply through contamination with plastics, dyes, and herbicides. Individual susceptibility would be influenced by the ability to metabolize the toxic chemical. Slow acetylators, for example, are more prone to hydralazine-induced SLE.
Bardana et al reported on autoimmune reactions induced by dietary antigens. They recalled that Sr. Wm. Osler had first suggested that dietary proteins were important in the pathogenesis of Henoch-Schonlein purpura and arthritis. They reported on an investigation of alfalfa-induced illness in monkeys A non-nutrient amino acid, L-canavanine, found in alfalfa seeds and sprouts, was identified as a trigger of an SLE-like syndrome. The severity of illness produced by canavanine in monkeys is remarkable; a hemolytic anemia was a consistent effect. Cooking alfalfa-containing foods may remove the problem since canavanine is heat labile.
In SLE-prone mice, removing milk protein, casein, from a standard laboratory diet had a dramatic benefit - 8% of the casein-fed mice survived at 24 months; 100% of the casein-free group survived. When the milk protein, casein, is digested, protein fragments or peptides can be potent players in immune networks. A casein peptide, beta-casomorphin 4-9, stimulates immune activity, creating hypersensitivity.
The Key Points...
We think that inflammatory arthritis is often caused by immune responses to food materials and encourage everyone with arthritis to give diet revision a try.
We urge the reader to spend the time required to understand good scientific hypotheses which lead to practical, common sense approaches to diet management in arthritis.
You are at Alpha Online, the host of the Inflammatory Arthritis Center. The topics are from the book, Managing Arthritis by Stephen Gislason MD. Alpha Education books refer to the Alpha Nutrition Program, a standard method of diet revision.
The Arthritis Nutritional Starter Pack includes
Order Books Online
Click the book title in the center column of the table (below) for more information. Click the Add to Cart button on the left to begin your order for printed books - mail delivery from Alpha Online. (US and Canada) Click the Download button to order PDF book files for download .
All Alpha Online nutrient formulas, printed books and starter packs are ordered online. Alpha Online ships through the Post Office to all destinations in Canada, Continental USA, Alaska, Hawaii. Prices are listed in Canadian dollars. Alpha Nutrition ® is a registered trademark and a division of Environmed Research Inc., Sechelt, British Columbia, Canada. In business since 1984. Online since 1995. Persona Digital has a separate book catalogue.