BLOOD GROUPS AND IMMUNITY III:
Auto-immunity, inflammation and the agglutinins (lectins, selectins, cadhesins, integrins)
PETER J. D'ADAMO
Copyright 2000-2001 All Rights Reserved. Unauthorized reproduction prohibited by law.
Lectins and immunity
While it is relatively easy to describe what a lectin does, they represent such a large and diverse class of naturally occurring molecules that it would be impossible to come up with a description of any one lectin that would fit all others. In a simple sense, a lectin is a protein-based molecule with a ‘sweet tooth.’ By this we mean that most lectins are comprised at least in part by proteins synthesized by the living organism than made it. Lectins like to attach to carbohydrates, mainly sugars or glycoproteins. Many of these carbohydrates are found on the exterior walls or membranes of simple cells, where they constitute the outer markers, or antigens, of that living creature. The great majority of the plant lectins are present in seed cotyledons where they are found in the cytoplasm or in the protein bodies, although they have also been found in roots, stems and leaves. Not surprising, many of these seeds, stems and leaves are components of many common foodstuffs. Thus lectin ingestion as part of any normally balanced diet is virtually unavoidable.
Until recently, it was not recognized that nature could employ sugars for the synthesis of highly specific compounds that can act as carriers of biologic information. Monosaccharides can servo as "letters" vocabulary of biologic specificity, where the words are formed by variations In the nature of the sugars present, the type of linkage, and the presence or absence of branch points. The first proof that sugars could serve as specificity determinants came from the discovery that influenza virus could agglutinate red cells only in the presence of certain membrane-bound carbohydrates. It these were removed, the virus no longer could bind to the cell. Sugars on cell surfaces also seem to determine the distribution of the circulating cells within the body. Radioactively treated rat lymphocytes will migrate to the spleen when re-injected into the animal. However if the sugar fucose is removed from the surface of the cells before reintroduction, the cells migrated to the liver instead, as if the fucose served as a ZIP code - directing the calls where to go. It was not until 1953 that we discovered that the specificity of the ABO blood group-system was determined by similar sugars. For example, the difference between blood types A and B lies in a simple sugar unit that sticks out from the end of a carbohydrate chain of a glycoprotein or glycolipid. In blood type A the determinant is acetylgalactosamine, in type O it is fucose, and in group B it is galactose.
When a lectin contains multiple binding sites, they can interconnect large numbers of cells, causing them to clump together or agglutinate. Each molecule of a lectin has two or more regions, perhaps clefts or grooves, each of which fits a complementary molecule of a sugar or several sugars. It is by means of these combining sites that the lectin attaches itself to the sugars on cell surfaces. Bacteria typically attach to prospective host cell membranes via receptors with lectin-like sugar specificity. This is of great importance, as the adherence of bacteria to host tissue surfaces is the initial event in a bacterial infection. Salmonella and Escherichia coli both carry several surface lectins with pronounced immunosuppressive ability. Both adhere to epithelial cells by attaching to the sugar mannose on the victim cell’s surface.
The attachment of lectins can often be blocked by the use of sugars specific to the lectin as a sort of ‘sacrificial molecule.’ For example, colonization of the urinary tract with E. Coli can markedly be reduced by the administration of mannose sugars, which is probably why cranberry juice works in preventing bladder infections, since it is an excellent source of mannose.
Naturally occurring agglutinins were first identified in 1888 at the University of Dorpat in Estonia. While investigating the toxic effects on blood of castor bean extract (Ricinus communis) it was noticed that the red cells were being agglutinated. The material responsible for the agglutination was isolated and called ricin. Shortly afterward at the same university it was discovered that the toxic extract of the seed Abrus precatoris also caused cells to clump together. This new agglutinin was called abrin. This immediately caught the attention of the German bacteriologist Paul Ehrlich who recognized that he could investigate certain immunologic problems with them rather than the then-popular bacterial toxins. With these two agglutinins some of the most basic principles of immunology were discovered. In 1908 Karl Landsteiner, who also discovered the basic ABO blood types, reported that small amounts of lentil lectin would agglutinate rabbit erythrocytes, even high concentrations of the lectin had no effect on pigeon red cells. Due to their peculiar properties, the lectins are used as a tool both for analytical and preparative purposes in biochemistry, cellular biology, immunology and related areas. In agriculture and medicine the use of lectins greatly improved in the last few years.
In 1945 William Boyd of the Boston University School of Medicine discovered that lectins can be blood group specific; some lectins being able to agglutinate the red cells of one type but not those of another. He discovered that lima bean lectin would agglutinate red cells of human blood type A but not those of O or B. It was Boyd who also was the first to coin the term ‘lectin’ which is Latin for legere, or ‘to choose.’ The seeds of Lotus Tetragonobolus can agglutinate group O specifically, and Bandairaea simplicofolia is specific to group B. The specificity of lectins is so sharply defined that they can differentiate among blood subgroups. Dolichos biflorens lectin reacts more vigorously with blood group Al than A2. Other blood groups can be distinguished by lectins, such as M and N blood types.
There is evidence that lectins may be involved in the recognition between cells or cells and various carbohydrate- containing molecules. This suggests that they may be involved in the regulating physiological functions. They seem to play an important role in the defense mechanisms of plants against the attack of microorganisms, pests, and insects. Fungal infection or wounding of the plant seems to increase lectins. Lectins are believed to be nature's own insecticides and because of this, they have attracted the attention of scientists who are genetically engineering them to produce food plants, containing specific lectins, which will not only have an insecticide effect, but on ingestion will also be 'hostile' to harmful bacteria in the human and animal gut. But that is another story.
It has increasingly been shown that the body uses lectins (or lectin-like molecules) to accomplish many of its most basic functions, including cell-to-cell adherence, the control of inflammation and the spread of cancer cells and even the programmed death of certain specific cells of the immune system. Let’s take a look at a few lectin like molecules currently under intense study:
Not all lectins are found in plants and seeds, A subset of lectins widely distributed from lower invertebrates to mammals are called galectins. In the last few years significant experimental data have been accumulated concerning their participation in different biological processes requiring carbohydrate recognition such as cell adhesion, cell growth regulation, inflammation, immunomodulation and cancer metastasis.
Evidence suggests that the galectins could be implicated in ‘programmed cell death’ of T-lymphocytes, a phenomena termed apoptosis. Cell death programming promotes immune tolerance by destroying hyper-reactive lymphocytes and terminating out-of-control immune responses. Although it is beyond the scope of this book to go into detail, suffice it to say that lymphocytes are susceptible to positive and negative selection by their interaction with galectins. T lymphocytes that fail to receive galectin stimulation (‘neglected cells’) undergo a default ‘cell death’ program. The remaining T cells are positively selected to survive.
BLOOD TYPE NOTE:
Galectins have been known to bind IgE on the cells of the pancreas which produce insulin. They also can bind the blood type A and B antigens at the same time. Since IgE initiates the basic allergic reaction with all its pro- inflammatory results, it is not unrealistic to speculate that the reactions to cows milk proteins that have been shown to sometimes result in juvenile diabetes may have a blood type component to them as well, since type I (juvenile diabetes) has a higher incidence in types B and A over O.
Smetana K, Holikova Z, Klubal R, Bovin NV, Dvorankova B, Bartunkova J, Liu FT, Gabius HJ. Coexpression of binding sites for A(B) histo-blood group trisaccharides with galectin-3 and Lag antigen in human Langerhans cells. J Leukoc Biol 1999 Oct;66(4):644-9
A subclass of lectins, called selectins are a family of cell adhesion molecules. Selectins mediate the binding of leukocytes to the walls of the blood vessels. This is an essential first step in white blood cells’ migration into tissue. The binding of selectin to the white blood cell generates signals that can result in initiating the inflammatory response. Once activated the cascade eventually results in a full blow inflammatory response.
Inflammation is a physiological response necessary for survival. In the absence of selectin inflammatory cells can not adhere to activated cells lining the blood vessels when blood flow is sufficiently high. Thus, selectins initiate inflammation on wall of blood vessels. Under-production of selectins is equivalent to an immune deficiency while over-production can mimic many inflammatory diseases.
During dissemination of cancer cells, adhesion to the blood vessel wall, which is essential for metastatic cells to migrate to distant sites, may involve selectins. The expression of these molecules has been reportedly increased on cells of the small vessels adjacent to primary colon and rectal tumors. Since selectins can bind epidermal growth factor, which in turn has been shown to bind with the blood type A antigen, this may be a possible explanation why individuals who are type A have been shown to have higher incidences of several common cancers.
BLOOD TYPE NOTE
One of the selectins, the IgE binding protein Epsilon BP, can mediate the binding of IgE to a diverse number of different tissues, including the insulin producing Langerhans cells of the pancreas. This lectin appears to bind cells that carry the A or B blood type antigen over cells that carry the H (O blood type) antigen. Since this lectin activates masts cells that can then degranulate, releasing cytotoxic inflammatory chemicals, it may help explain why juvenile diabetes appears to have a preference for A and B blood types over type O.
Feizi T, Solomon JC, Yuen CT, Jeng KC, Frigeri LG, Hsu DK, Liu F. The adhesive specificity of the soluble human lectin, IgE-binding protein, toward lipid-linked oligosaccharides. Presence of the blood group A, B, B-like, and H monosaccharides confers a binding activity to tetrasaccharide (lacto-N-tetraose and lacto-N-neotetraose) backbones. Biochemistry 1994 May 24;33(20):6342-9
The cadherins establish molecular links between adjacent cells by means "zipper-like structures" at membrane regions where a cell makes contact with other cells. Thus cadherins are essential to the architecture of the body; without them cells could not aggregate into larger structures, such as organs.
The expression of cadherin molecules in the embryo is crucial for the migration of cells and the differentiation of tissues. As one might expect, cadherins are crucial for the maintenance of epithelial structure -One can imagine what loss of epithelial cell to cell adhesion would be like. It can be similar to losing the glue that holds the epithelial cells together.
Since cancer cells tend to spread by losing their ability to adhere to their base tissue, not surprisingly, cadherins are the subject of considerable study with regard to cancer metastasis. The initial step of cancer metastasis is the detachment of cells from the primary tumor mass. In tumors of epithelial origin, the loss of cadherin's self-adherence function is directly proportional to the probability that that tumor will metastasize. Indeed, under normal conditions with sufficient activity of cadherins, cells are unable to disrupt their mutual connections; only in the state of cadherin inactivation may a cells be freed from its adhesive constraints and migrate out of its parent colonies. In fact reduced cadherin levels have been observed in a broad range of malignancies, including cancers of the head and neck, lung, breast, prostate, oesophagus, stomach and colorectum. Clinical studies suggest that the loss of E-cadherin function is directly associated with tumor invasion and metastasis. In gastric carcinoma, highly differentiated tumors generally maintain homogeneous, strong expression of cadherin, while in more invasive tumors cadherin expression is found to be altered or even completely suppressed.
The integrins are a large family of molecules that control a variety of cell-to-cell and cell-to-outside world interactions. Their role appears to be more dynamic than the cadherins, which are simply adhesive in nature. Certain of the integrins control the adhesion of white blood cells to the lining of the blood vessels, while some others bind to inflammatory proteins involved in wound healing. Several integrins control the of laying down new blood vessel networks a process called angiogenesis. In growth and wound healing this process is switched on and off, while some tumors apparently have evolved a method to inhibit this signal.
BLOOD TYPE NOTE
Since many integrins have a binding site for epidermal growth factor in addition to a lectin binding site, and epidermal growth factor can be mimicked by the blood type A antigen. This may help explain why it has been reported that individuals who are blood type A have a much higher incidence of hemangiomas of the liver (benign tumors characterized by extravagant capillary networks of blood vessels.) Since many tumors shown to be more common in blood type A, such as tumors of the breast, are sensitive to treatments that involve inhibiting the tumors’ ability to develop additional blood supplies (anti-angiogenesis) the effect of one’s A antigen on such tumors would exert a profoundly negative effect.
Polysalov VN, Tarazov PG. [Blood group assignment--a genetic marker of hepatic hemangiomatosis]. Genetika 1992 Jul;28(7):161-4
BLOOD TYPE NOTE:
Soy isoflavones, including genestein, inhibit angiogenesis -another good reason for type A’s to get enough soy based proteins into their diet.
Kapiotis S, Hermann M, Held I, Seelos C, Ehringer H, Gmeiner BM Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells from damage by atherogenic LDL. Arterioscler Thromb Vasc Biol 1997 Nov;17(11):2868-74
Inflammation: Collateral damage
The word inflammation literally means ‘a burning’ and has been in the medical literature since the first century A.D. when the Roman physician Celsus formulated his famous cardinal signs of inflammation: calor (heat) ruber (redness) tumor (swelling) and dolor (pain). To this list, the famous German pathologist Rudolf Virchow added functio laesa (loss of function).
Within every living cell inflammation is a biochemical and cellular time bomb waiting to go off. Yet inflammation in itself is neither ‘good’ nor ‘bad’: more people die from an inflammatory diseases than all other disease processes combined; just ponder for a moment the huge number of medical conditions with the ending ‘-itis.’ Yet without an adequate inflammatory response by the body’s cells, we would not survive for long, since the inflammatory response is necessary for fighting infection and the normal healing of damaged tissue. The types of damage that induce inflammation include tissue damage, bone fracture, and injuries due to cuts, burns, infections and allergies.
One of the main reasons that the inflammatory process is vital to a living creature’s existence is that inflammation actually is closely integrated with the responses that constitute healing and repair of damaged tissue. Virtually all of the white blood cells (neutrophils, lymphocytes, eosinophils, basophils, and monocytes), as well as the blood clotting platelets and mast cells, are involved in the inflammatory response. The cells involved either contain or can produce more than 100 chemical mediators of the inflammatory response.
Inflammation directs the elements of the immune system into damaged tissues by increasing the blood supply to the infected area and increasing capillary permeability, processes that allow larger molecules to pass through the endothelial layer than would normally allowed so that new recruits can migrate into the affected area.
Cytokines playing important roles in inflammation include interleukin-1 (IL-1) and IL-6, which induce the release of acute phase proteins, such as complement and act as ‘fever producers’ or pyrogens. Tumor necrosis factor causes leukocytes to adhere to the walls of the blood vessels by promoting the expression of adhesion molecules, such as the selectins. Once the leukocytes adhere, they are stimulated to migrate further by other chemical attractants being produced by cells already at the injury site. Most of the cells of the inflammatory response are phagocytic. The polymorphonuclear leukocytes (mainly neutrophils) accumulate within the first 30-60 minutes, followed by a mononuclear cell infiltrate (consisting of macrophages and lymphocytes) within the next 5-6 hours. If the inflammation is due to infection, the initial response will be the phagocytic cells of innate immunity, which will attach to the microbes nonspecifically, or through receptors for complement or antibody if these have already coated the interloper. Once attached, the phagocytic cells extend long arms of the cell bodies around the virus or bacteria until they connect, forming a sac inside the cell filled with the microbe. At that point the white blood cell begins to pump in powerful enzymes which effectively can kill the microbe. These enzymes are a class called lysozymes or peroxidases, and work by producing a highly reactive species of oxygen that can fuse with the outer membranes of bacteria, or directly destroy the genetic material of bacteria and viruses.
If the infection persists, the phagocytic response will be supplemented by the elements of acquired immunity, such as antibodies and mast cells with their packets of histamine granules. Histamine is a prominent player in many types of inflammation, including allergy. The antihistamine drugs that many depend on during an allergy season are acting effectively as anti-inflammatories by reducing the production of histamine.
The protracted process of inflammation can often be more harmful than the event that originally stimulated it. A system of such complexity, with so many different players can be difficult to control. Many chemicals involved in the immune response are very caustic, as their main purpose to kill the invader. However, if the reaction is intense, there can be a spill over of such chemicals which results in damage the tissue in the area as well.
Inflammation also results when tissue injury activates blood clotting factors which promote the clotting or coagulation cascade. Through a multi-step process, the cascade results in the production of plasmin, which controls the dissolution of the clot and activates complement, and inflammatory kinins, which cause smooth muscle contraction, increase vascular permeability, induce adhesion molecule expression on endothelial cells, and cause pain and itching sensations.
BLOOD TYPE NOTE
Factor VII, one of the important clotting factors, and typically elevated in individuals who are blood type A (probably an important reason why this blood type has more problems with blood clots than the other types) is paradoxically elevated instead in blood type B when they are in the acute stage of inflammation. As in heart disease, the levels are lower in blood type O
O'Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D, Laffan M. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997 May;77(5):825-8
BLOOD TYPE NOTE
In a study looking at the immune response in the heart tissue of patients with rheumatic heart disease, individuals who were type O had the highest levels of antibody formation against heart mucle and connective tissue and overall levels of the inflammatory process. Blood type B had the lowest.
Motovilov AA. [Heterogenicity of the immune response to antigens of muscular and interstitial connective tissue of the heart in patients with rheumatic diseases. II. Association with ABO antigens]. Vestn Akad Med Nauk SSSR 1989;(9):80-5
BLOOD TYPE NOTE
Blood type B appears to be protective against certain types of reactive arthritis (arthritis resulting from an infectious cause).
Tertti R, Jarvinen H, Lahesmaa R, Yli-Kerttula U, Toivanen A AB0 and Lewis blood groups in reactive arthritis. Rheumatol Int 1992;12(3):103-
BLOOD TYPE NOTE
Blood type A seems to have a protective influence on the progression of ankylosing spondylitis
Bauer K . Evidence for a protective influence of blood group A phenotype on X-ray signs of ankylosing spondylitis in HLA-B27 positives. Dis Markers 1987 Sep;5(3):187-8
BLOOD TYPE NOTE
Researchers examined 52 patients with gunshot wounds of various localization. It is shown that such signs of constitutional immunity as the B blood group, weak phagocytosis intensity, and low saturation of the connective tissue with ascorbic acid are risk factors of purulent complications in both traumatic and gunshot wounds.
Shaposhnikov IuG, Tabatadze KG, Zhukova OV, Kondrat'eva IE, Filianin AM, Rychkov IuG. [Wound healing as affected by constitutional immunity factors]. Khirurgiia (Mosk) 1991 Jul;(7):23-7
BLOOD TYPE NOTE
ABO frequencies are reported in a series of 341 patients undergoing total hip replacement for primary osteoarthritis. Compared to a control group of blood donors from the same geographical area there is a significant deficit of group O among the arthritic patients. It is suggested that there may be a heritable component in the susceptibility to develop osteoarthrosis in an otherwise normal hip-joint.
Lourie JA. Is there an association between ABO blood groups and primary osteoarthrosis of the hip? Ann Hum Biol 1983 Jul-Aug;10(4):381-3
BLOOD TYPE NOTE
Gram negative bacteria precipitate reactive arthritis and may be concerned in the pathogenesis of ankylosing spondylitis and other spondyloarthropathies. Susceptibility to many infectious agents is associated with ABO blood group or secretor state, or both. The association between non-secretor state and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis is a form of reactive arthritis. It also suggests several pathogenic mechanisms which may be relevant to the initial host parasite interaction in ankylosing spondylitis.
Shinebaum R, Blackwell CC, Forster PJ, Hurst NP, Weir DM, Nuki G. Non-secretion of ABO blood group antigens as a host susceptibility factor in the spondyloarthropathies. Br Med J (Clin Res Ed) 1987 Jan 24;294(6566):208-10
BLOOD TYPE NOTE
One of the reasons that blood type O individuals are more prone to inflammatory problems may have to do with the fucose sugar which acts as their blood type antigen. Fucose sugars serve as adhesion molecules for lectin-like molecules found on white blood cells (selectins) which allow for migration of white blood cells from the blood stream into the areas of inflammation.
Listinsky JJ, Siegal GP, Listinsky CM. Alpha-L-fucose: a potentially critical molecule in pathologic processes including neoplasia. Am J Clin Pathol 1998 Oct;110(4):425-40
BLOOD TYPE NOTE
In patients suffering from infection with the ulcer-causing bacteria addition Helicobacter pylori, blood group O non-secretors had a significantly higher grade of lymphocyte infiltration of their gastric mucosa compared to non-O non-secretors
Heneghan MA, Moran AP, Feeley KM, Egan EL, Goulding J, Connolly CE, McCarthy CF. Effect of host Lewis and ABO blood group antigen expression on Helicobacter pylori colonisation density and the consequent inflammatory response. FEMS Immunol Med Microbiol 1998 Apr;20(4):257-66
BLOOD TYPE NOTE
There is a relationship between secretor state and the inflammatory response to urinary tract infection (UTI). Girls with recurrent UTI were prospectively studied. They included 61 secretor and 23 non-secretor individuals with 604 episodes of recurrent UTI.. The levels of C-reactive protein, erythrocyte sedimentation rate and the body temperature were significantly higher in non-secretors than in secretors (p less than 0.04). The higher inflammatory response in non-secretors might explain the accumulation of these individuals among patients with renal scarring.
Lomberg H, Jodal U, Leffler H, De Man P, Svanborg C. Blood group non-secretors have an increased inflammatory response to urinary tract infection. Scand J Infect Dis 1992;24(1):77-83
The word "auto" is the Greek word for self. If a person has an autoimmune disease, the immune system mistakenly attacks self, targeting the cells, tissues, and organs of a person's own body. There are many different autoimmune diseases, and they can each affect the body in different ways. For example, the autoimmune reaction is directed against the brain in multiple sclerosis and the gut in Crohn's disease. Ultimately, damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus.
Much of the damage done by autoimmune disease is the result of immune complexes, an insoluble lattice network of antibodies bound to antigens in the bloodstream. Immune complexes are harmful when they accumulate and initiate inflammation. Immune complexes, immune cells, and inflammatory molecules can block blood flow and ultimately destroy organs such as the kidney in people with systemic lupus erythematosus, or the insulin secreting Isles of Langerhans in the pancreas.
One of the major jobs of the complement system is to remove immune complexes. The different types of molecules of the complement system make immune complexes more soluble. Complement molecules prevent formation and reduce the size of immune complexes so they do not accumulate in the wrong places, such as the organs and tissues of the body.
Many of the autoimmune diseases are rare. As a group, however, autoimmune diseases afflict millions of Americans. Most autoimmune diseases strike women more often than men; in particular, they affect women of working age and during their childbearing years. Some autoimmune diseases occur more frequently in certain minority populations. For example, lupus is more common in African-American and Hispanic women than in Caucasian women of European ancestry. Rheumatoid arthritis and scleroderma affect a higher percentage of residents in some Native American communities than in the general U.S. population.
BLOOD TYPE NOTE
In general non-secretors have much higher incidences of auto-immune disease over secretors, espoecially when the provocative event was an infection.
Blackwell CC. The role of ABO blood groups and secretor status in host defences. FEMS Microbiol Immunol 1989 Jun;1(6-7):341-9
BLOOD TYPE NOTE:
Stinging nettle root (Urtica dioica rhizome) contains a small-molecular-weight lectin (Urtica dioica agglutinin) purified from the root, which is capable of modulating aspects of the immune system. The lectin in Urtica dioica might beneficially modulate an overactive immune system by reducing tumor necrosis factor-alpha and interleukin-1 beta. The lectin in Urtica root (UDA) is a T-cell mitogen, with the ability to discriminate a particular population of CD4+ and CD8+ T-cells which results in an increase in immune tolerance. Probably due to its ability to alter the production of anti-self antibodies, the lectin in Urtica root has been shown to protect the kidneys and cardiovascular system from the progression of experimentally induced autoimmune damage in mice. Use of this lectin should be avoided in blood types AB or B as there are reports that the lectin agglutinates red blood cells carrying the B antigen.
Obertreis B, Ruttkowski T, Teucher T, et al. Ex-vivo in-vitro inhibition of lipopolysaccharide stimulated tumor necrosis factor-alpha and interleukin-1 beta secretion in human whole blood by extractum Urticae dioicae foliorum. Arzneimittelforschung 1996;46:389-394.
Galelli A, Truffa-Bachi P. Urtica dioica agglutinin. A superantigenic lectin from stinging nettle rhizome. J Immunol 1993;151:1821-1831.
Galelli A, Delcourt M, Wagner MC, et al. Selective expansion followed by profound deletion of mature V beta 8.3+ T cells in vivo after exposure to the superantigenic lectin Urtica dioica agglutinin. J Immunol 1995;154:2600-2611.
Musette P, Galelli A, Chabre H, Callard P, Peumans W, et al. Urtica dioica agglutinin, a V beta 8.3-specific superantigen, prevents the development of the systemic lupus erythematosus-like pathology of MRL lpr/lpr mice. Eur J Immunol 1996;26:1707-1711.
Unlike adult onset diabetes (type II) which is a gradual loss of sensitivity to insulin, juvenile diabetes (type I) is characterized by destruction of the cells which are responsible for the secretion of insulin. Increasing evidence is pointing to the fact that, though there is a considerable link genetically in families, type I diabetes may be (at least initially) an autoimmune disease.
In general type I diabetes has a highly significant overall association with blood types A and AB, and this is especially strong in males versus females. What is especially interesting, is the fact that the percentage of blood type A over blood type O in diabetes appears to increase with age. This association has been confirmed in several large independent studies, looking at literally thousands of people.
Sidhu LS, Malhotra P, Singh SP. ABO and Rh blood groups in diabetes mellitus. Anthropol Anz 1988 Sep;46(3):269-75
Mourant AE. Blood Groups and Disease. Oxford Press
It is my theory that the link with blood type A and diabetes results from the ability of certain serum lectins to bind to both the A antigen and the insulin producing Langerhans cells of the pancreas. This complex has been shown to stimulate the activation of the antibody IgE at the site, thereby resulting in inflammation and cell death. This would explain why both blood types that carry an A antigen are at risk.
The occurrence of blood type A has also been shown to be elevated in individuals who have ‘borderline diabetes’ i.e insulin levels low, but not frankly absent.
Kanazawa Y, Furusho T, Nakajima H, Amemiya S, Akanuma Y, Kosaka K. Blood groups and diabetes mellitus: a possible tool in the analysis of the hereditary background of diabetes mellitus. Tohoku J Exp Med 1983 Dec;141 Suppl:295-9
Non-insulin-taking diabetics show an increased frequency of blood type A when compared with controls. This difference is particularly marked in male diabetics. When diabetics are compared with age matched controls, the difference is confined to the older cases.
Williams DR, Cartwrigth RA. Genetic polymorphisms in diabetics and non-diabetics. J Med Genet 1979 Oct;16(5):351-7
One of the strongest risk factors for juvenile diabetes, almost the same risk as having a mother with diabetes is a maternal-child blood group incompatibility. As we have seen, the immune consequences of maternal-fetal incompatibility are the worst if the mother is blood type O and the child is blood type A. This association was particularly strong for children of ABO incompatible mothers who went on to develop diabetes within the first five years of life.
Dahlquist G, Kallen B. Maternal-child blood group incompatibility and other perinatal events increase the risk for early-onset type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1992 Jul;35(7):671-5
Interestingly, diabetes may have exerted a powerful environmental effect on the delayed occurrence of blood type A in any large numbers. To understand why, let’s first begin by asking ourselves the question ‘if diabetes is a fairly deadly disease without insulin replacement, how could it have persisted genetically through the earlier times in which there was no effective life-saving therapy? Several theories have been advanced, including the observation that women who have a hereditary tendency toward diabetes tend to be more fertile than normal women, and apparently begin to menstruate younger.
Ascher and Post (1956) In Mourant Blood groups and Disease
Post and White (1958) In Mourant Blood groups and Disease
In the late 1950’s it was put into a broader anthropological context, with the observance that in Paleolithic times, when man lived on a low carbohydrate, low calorie diet, diabetes would have only rarely developed to the point that the greater fertility would have maintained the frequency of the gene, and indeed one researcher went so far as to call diabetes a ‘thrifty gene’ which may have had some advantage to those possessing it, especially during times of starvation. Thus diabetes may have been at one time advantageous under primitive conditions, but with the availability of adequate (or more than adequate) carbohydrate-rich diets, it now gives rise to a different sort of result altogether.
BLOOD TYPE NOTE
This is especially interesting in light of research which seems to indicate that although the overall incidence of diabetes is higher in blood type A, the percentage of blood type O rises in diabetics who are below average in weight.
Scholz W, Knubmann R, Daweke H. Distribution of blood and serum protein group characteristics in patients with diabetes. Diabetologia 1975 Feb;11(1):77-82
BLOOD TYPE NOTE
As with stress, high blood pressure and myocardial disease, there are substantial differences between blood type A and blood type O diabetics with regard to the rheology (fluidity) of their blood. Blood type A diabetics have significantly higher levels of clotting factors in their blood when compared with blood type O or blood type B diabetics. This may be an important risk factor in determining chances of developing cardiovascular complications due to diabetes
Dintenfass L, et al. Genetic and ethnic influences on blood viscosity and capillaries in diabetes mellitus. Microvasc Res. 1977 Sep;14(2):161-72.
Several dietary lectins, including wheat germ agglutinin, can bind to insulin secreting pancreatic islet cells and initiate an antibody response.
Kitano N, Taminato T, Ida T, Seno M, Seino Y, Matsukura S, Kuno S, Imura H. Detection of antibodies against wheat germ agglutinin bound glycoproteins on the islet-cell membrane. Diabet Med 1988 Mar;5(2):139-44
Common mushrooms, a traditional remedy for diabetes, have a lectin which can help to stimulate the production of insulin.
Permutt MA, et al Insulin biosynthesis and secretion. Fed Proc. 1975 Jun;34(7):1549-55.
Gray AM, et al. Insulin-releasing and insulin-like activity of Agaricus campestris (mushroom). J Endocrinol. 1998 May;157(2):259-66.
Swanston-Flatt SK, Day C, Flatt PR, Gould BJ, Bailey CJ Glycaemic effects of traditional European plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice. Diabetes Res 1989 Feb;10(2):69-7
BLOOD TYPE NOTE
Non-secretors are more prone to type II (insulin resistant) and type I (insulin dependant) diabetes over secretors. Non-secretors who were type I diabetics were shown to have much more consistent problems with the yeast Candida albicans, especially in their mouth and upper GI tract.
Blackwell CC, Aly FZ, James VS, Weir DM, Collier A, Patrick AW, Cumming CG, Wray D, Clarke BF
Blood group, secretor status and oral carriage of yeast among patients with diabetes mellitus. Diabetes Res 1989 Nov;12(3):101-4
BLOOD TYPE NOTE
Many patients with type I diabetes have low levels of complement in the blood stream. As we’ve discussed, one of the major roles of complement is to help remove the immune complexes that are the major cause of tissue damage in auto-immune disease. It is interesting to note that the gene that controls whether we are a secretor or non-secretor is in the same linkage group as is the gene that controls for the C3 complement component –the same complement protein responsible for removal of immune complexes. Since they are at a genetic disadvantage with removing immune complexes, it is no surprise that non-secretors have more auto-immune disease than secretors –and more diabetes.
Blackwell CC, Weir DM, Patrick AW, Collier A, Clarke BF. Secretor state and complement levels (C3 and C4) in insulin dependent diabetes mellitus Diabetes Res 1988 Nov;9(3):117-9
Autoimmune Thyroid Diseases
The thyroid gland affect many parts of the body. Hashimoto's thyroiditis and Grave's disease result from immune system destruction or stimulation of thyroid tissue. Symptoms of low (hypo) or overactive (hyper) thyroid function are nonspecific and can develop slowly or suddenly; these include fatigue, nervousness, cold or heat intolerance, weakness, changes in hair texture or amount, and weight gain or loss. The diagnosis of thyroid disease is readily made with appropriate laboratory tests.
The symptoms of hypothyroidism are controlled with replacement thyroid hormone pills; however, complications from over- or under-replacement of the hormone can occur. Treatment of hyperthyroidism requires long-term anti-thyroid drug therapy or destruction of the thyroid gland with radioactive iodine or surgery. Both of these treatment approaches carry certain risks and long-term side effects. Autoimmune thyroid diseases afflict as many as 4 out of 100 women and are frequently found in families where there are other autoimmune diseases.
One of the more important inflammatory molecules of the immune response is fibrinogen, an acute phase reactant (like complement) which increases in concentration in response to trauma, tissue inflammation,
and pregnancy as well as the introduction of biological stimulators as growth hormone, inflammatory prostaglandins, and certain bacterial toxins. Fibrinogen is produced by the liver and taken up by the platelets. Fibrinogen is a tenacious molecule which rapidly finds its way to a variety of surfaces including foreign materials and the underlayment of the blood vessels. During inflammation, fibrinogen escapes into the tissues where it is converted into fibrin
BLOOD TYPE NOTE
As with stress, myocardial infarction, diabetes and certain malignancies, thyroid disease is characterized by viscosity (thickness) differences between the blood types, especially when blood type A is compared to blood type O. Blood type A subjects with thyroid disease had higher levels of fibrinogen and a lower albumin/fibrinogen ratio when compared to blood type O. Since the inflammatory processes of the body use fibrinogen, Von Wildebrand Factor and Factor VIII as ‘adhesive glues’ to form a matrix collagen, platelets and fibrin.
Dintenfass L, et al . Effect of fibrinogen on aggregation of red cells and on apparent viscosity of artificial thrombi in haemophilia, myocardial infarction, thyroid disease, cancer and control systems: effect of ABO blood groups. Microvasc Res. 1975 Jan;9(1):107-18.
BLOOD TYPE NOTE
Since the long term effect of this type of inflammatory activity would be the gradual replacement of healthy functioning thyroid tissue with instead metabolically inactive scar tissue, it may help explain why hypothyroidism is associated with blood type A, especially when in combination with pernicious anemia- another disorder associated with blood type A. Hyperthyroidism, at least in patients with pernicious anemia, on the other hand, is more often seen in blood type O.
Carmel R, Spencer CA . Clinical and subclinical thyroid disorders associated with pernicious anemia.
Observations on abnormal thyroid-stimulating hormone levels and on a possible association of blood group O with hyperthyroidism. Arch Intern Med 1982 Aug;142(8):1465-9
BLOOD TYPE NOTE
Hyperactive thyroid tissue is much more sensitive to the agglutinating effects of lectins found in wheat and soybeans than healthy thyroid tissue. Perhaps this explains why several very exciting outcomes reported on my website reported that their Hashimoto’s Thyroiditis went into spontaneous complete remission by simply following the blood type diet. In every case the person was blood type O, so I am left to speculate that the low lectin diet somehow had the effect of removing a necessary factor in the continued inflammatory response. This may also be due to the fact that while a normal thyroid does not normally express large amounts of blood type antigens, a sick one can generous enormous amounts. Thyroid tissue that is inflamed generates large amounts of the blood type A antigen, which of course would be a major problem if you carried anti-A in your serum, particularly if you are type O and not only make IgM anti-A, but IgM anti-A,B, IgG anti-A and IgG anti A,B!
Davidson H Lectin histochemistry of the thyroid gland.. Gonzalez-Campora R, Sanchez Gallego F, Martin Lacave I, Mora Marin J, Montero Linares C, Galera- Cancer 1988 Dec 1;62(11):2354-62
Gonzalez-Campora R, Sanchez Gallego F, Martin Lacave I, Mora Marin J, Montero Linares C, Galera-Davidson H Lectin histochemistry of the thyroid gland. Cancer 1988 Dec 1;62(11):2354-62
Wick MR, Sawyer MD Antigenic alterations in autoimmune thyroid diseases. Observations and hypotheses. Arch Pathol Lab Med 1989 Jan;113(1):77-81
Another possibility is that the low lectin diet and the subsequent lowering of polyamines in the intestines may have the effect of diminishing hyperactivity in the thyroid; studies have shown that ABO antigen expression in the thyroid closely parallels ABO antigen expression in the colon.
Vowden P, Lowe AD, Lennox ES, Bleehen NM Thyroid blood group isoantigen expression: a parallel with ABH isoantigen expression in the distal colon. Br J Cancer 1986 Jun;53(6):721-5
White kidney bean (P. vulgaris) has been shown to suppress experimental auto-immune thyroiditis in mice for up to 7 weeks
Freed DJ. ‘Dietary Lectins’ in Food Allergy and Intolerance Brostoff and Challcombe, ed.
BLOOD TYPE NOTE
Several fairly common auto-immune disorders appear to be characterized by inappropriate production of anti-blood type isoagglutinin antibodies.
BLOOD TYPE NOTE: PEMPHIGUS AND LUPUS
The auto immune diseases pemphigus and systemic lupus erythematosis (a disease with a proclivity for blood type B) were shown to be characterized by inappropriate isohemagglutinin response to stimulation with A or B antigens.
Stringa SG, Bianchi C, Andrada JA, Comini E, Gaviglio AM, Casala A. Immunologic response to A and B erythrocytic antigen. Arch Dermatol 1976 Apr;112(4):489-92
Ottensooser F, Leon N, de Almeida TV. ABO blood groups and isoagglutinins in systemic lupus erythematosus. Rev Bras Pesqui Med Biol 1975 Sep-Dec;8(5-6):421-5
BLOOD TYPE NOTE: SCLERODERMA
When 16 schleroderma patients were immunized with incompatible blood groups substances of their ABO system yielded distinct increases in their isohemagglutinin when compared against 16 controls.
Haustein UF, Beckmann I, Haustein B, Lewandowski A. Immunologic reactivity to incompatible blood group substances of the ABO system in scleroderma. Acta Biol Med Ger 1975;34(8):1417-20
LECTIN NOTE: FIBROMYALGIA
Of the various food which have been show to induce joint inflammation, grains certainly top the list. One lectin researcher goes so far to say that ‘avoidance of these is frequently the only dietary maneuver required, especially in the early cases.’ As we have seen, many common grains contain lectins, and many of these lectins are specifically attracted to sugars, particularly N-acetyl glucosamine (NAG), that are found abundantly in connective tissue. Wheat germ lectin in particular has an affinity for NAG. Many cases of fibromyalgia have been helped by following the Blood Type Diet and my suspicion is that the majority of the improvement is simply the result of wheat avoidance, particularly in blood types A and O.
BLOOD TYPE NOTE: RHEUMATOID ARTHRITIS
There are several contradictory studies on the relative incidence of rheumatoid arthritis in the different blood types. One anecdotal reference from my father seems quite accurate. ‘If you look hard enough,’ he once told me ‘you’ll find that blood type A tends to get a puffy, inflamed arthritis, while type O tends to get a more harder, grittier type of arthritis.’ I tend to find this to be in general quite accurate. In general blood type A appears to get a more aggressive form of rheumatoid arthritis.
BLOOD TYPE NOTE: RHEUMATOID ARTHRITIS
Peptic ulcers developed in 33% of patients, all of whom had type O blood. ABO blood typing may therefore be useful in patients with rheumatoid arthritis before consideration of therapy with potentially ulcerogenic drugs.
Semble E, Metcalf D, Turner R, Agudelo C, Pisko E, Johnson AM, Heise E. Genetic predictors of patient response and side effects in the treatment of rheumatoid arthritis with a high dose nonsteroidal antiinflammatory drug regimen. Arthritis Rheum 1982 Apr;25(4):370-4
LECTIN NOTE: RHEUMATOID ARTHRITIS
Recent studies on the antibodies made against the joint tissue typically found in rheumatoid arthritis show that they differ from normal antibodies in an important fashion. Normal antibodies have the sugar galactose as the carbohydrate side chain. Antibodies in rheumatoid arthritis appear to be somewhat defective; instead of galactose, the carbohydrate on the side chain is n-acetyl glucosamine, the sugar for which wheat germ lectin is highly specific for. Apparently the adoption of a wheat free diet appears to have some effect in mollifying the effect of the antibody.
This also brings to mind the fact that perhaps the two sugars most commonly used in alternative medicine to treat arthritis, glucosamine and chondroitin (the so-called ‘Arthritis Cure’) may in fact have lectin blocking as the basis for their effectiveness. It is worth noting again that glucosamine binds wheat germ lectin very effectively, while chondroitin is merely the blood type A antigen in very long linkages (polymerized). In either case it is very likely that both function as ‘sacrifical molecules,’ reacting with lectins so as to prevent these same lectins from reacting with the inflamed tissue. Thus the chemical basis of the ‘Arthritis Cure’ may well be that it chemically mimicks the effect of a low-lectin diet
Freed DJ. Rheumatic Patches. http://www.elfstrom.com/arthritis/articles/r-patch.html
LECTIN NOTE: RHEUMATOID ARTHRITIS
The abberant antibody in rheumatoid arthritis, often called ‘galactose-free immunoglobulin’ has also been shown to have a high degree of reactivity with the lectin found in the common lentil (Lens culinaris). This is interesting in light of the fact that a very good experimental model of human rheumatoid arthritis can be produced in rabbits by injecting their joints with lentil lectin.
Tang W, Matsumoto A, Shikata K, Takeuchi F, Konishi T, Nakata M, Mizuochi T Detection of disease-specific augmentation of abnormal immunoglobulin G in sera of patients with rheumatoid arthritis.
Thoss VK, et al . [Lectin arthritis--a new arthritis model]. Glycoconj J 1998 Sep;15(9):929-34
LECTIN NOTE: MYASTENIA GRAVIS
Electrolectin, the galectin from the electric eel (Electrophorus electricus) was shown to prevent and effectively treat experimental auto-immune myastenia gravis in rabbits, considered a good model for the human disease myastenia gravis. Administration of electrolectin to the afflicted rabbits lead in all cases to recovery, presumably through the lectins’ stimulation of the suppressor cell activity directed against acetylcholine receptor self antibodies.
Bon S, et al. Interactions between lectins and electric eel acetylcholinesterase. FEBS Lett. 1975 May 15;53(3):282-6.
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