BLOOD GROUPS AND IMMUNITY II

Cytokines, Growth Factors and Antibodies

PETER J. D'ADAMO

Copyright 2000-2004 All Rights Reserved. Unauthorized reproduction prohibited by law.

The  relationship between  lymphocytes and   antigen-presenting cells is complicated and depends on  a  huge molecule   called the major histocompatibility complex (MHC) a sort of socket by which lymphocytes recognize and process foreign antigens. The biological role of MHC proteins is to bind small foreign antigens and to "present" these at the cell surface for the inspection by the T cell lymphocytes. Like blood type, the MHC is a molecular and genetic delineator of ‘self’: For example, It has a major influence on graft and organ transplant survival. Individuals identical for this region can exchange grafts more successfully than MHC non-identical combinations. It has been hypothesized that the MHC interacts with our blood type antigens in such day-to-day activities as cell-cell recognition, association and aggregation. The relationship appears to be quite important to the development of our immune system  during the ‘education’ of lymphocytes in the thymus gland. T-cells comprise 80% to 90% of circulating lymphocytes, and may survive up to 30 years. T-cells can be categorized as helper/inducer (CD4) cells and as suppressor/cytotoxic (CD8) cells.

T-helper cells: Like the name implies, T-helper cells respond to soluble antigen and ‘help’ induce B-lymphocytes to secrete antibodies.

T helper cells come in two flavors:

·     TH1 (inflammatory helper cells) produce cytokines that promote cellular  immune responses. These cytokines include  interleukin-2 (IL-2), interferon-gamma (IFNg), and  tumor necrosis factor-beta (TNFb),.

·     TH2 (helper cells) cells produce interleukins 2, 4 6 and 10, all of which  prompt  B cells to produce antibodies.

Cytotoxic or cytolytic T cells lyse (kill)  cells that produce foreign  antigens, such as tumor cells, virus-infected cells, and foreign tissue grafts Cytoxic T cells are identified by the presence of the CD8 marker. These cells can suppress the immune response, and are sometimes referred to as ‘Supressor-T cells.’

Growth factors

Growth factors are proteins that bind to receptors on the cell surface, with the primary result of activating cellular proliferation and/or differentiation. Many growth factors are quite versatile, stimulating cellular division in numerous different cell types; while others are specific to a particular cell-type.

Cytokines are a unique family of growth factors. Secreted primarily from leukocytes, cytokines stimulate both the humoral and cellular immune responses, as well as the activation of phagocytic cells. Cytokines that are secreted from lymphocytes are termed lymphokines, whereas those secreted by monocytes or macrophages are termed monokines. A large family of cytokines are produced by various cells of the body. Many of the lymphokines are also known as interleukins (ILs), since they are not only secreted by leukocytes but also able to affect the cellular responses of leukocytes. Specifically, interleukins are growth factors targeted to blood cells.

Let’s take a look at some of the more commonly known factors and their principal activities.

·     Epidermal Growth Factor (EGF)  EGF, like all growth factors, binds to very specialized receptors on the surface of responsive cells. Intrinsic to the EGF receptor is tyrosine kinase activity, which is activated in response to EGF binding.  EGF stimulates mesodermal and ectodermal origin, particularly of the skin and connective tissue. EGF inhibits certain carcinomas as well as hair follicle cells. EGF also has the effect of decreasing gastric acid secretion.

 Other growth factors include:

·    Interleukin-1 (IL-1)  IL-1 is one of the most important immune modifying interleukins. The predominant function of IL-1 is to enhance the activation of T-cells in response to antigen.

·    Interleukin-2 (IL-2) is  produced and secreted by activated T-cells and is the major interleukin responsible for T-cell proliferation. IL-2 also exerts effects on B-cells, macrophages, and natural killer (NK) cells. The production of IL-2 occurs primarily by CD4+ T-helper cells.

·    Interleukin-4 (IL-4) Induces B cell proliferation, eosinophil and mast cell growth and function, and IgE  expression on B cells. Allergic individuals have a greater propensity to produce IL-4. Many dietary lectins induce the activation of IL-4, which implies that for many people the allergic reaction to dietary lectins may be more important than their agglutinating abilities

·    Interleukin-8 (IL-8) IL-8 is an interleukin that acts as a ‘chemo-attractant’ for leukocytes and connective tissue cells. IL-8 is produced by monocytes, neutrophils, and NK cells and is acts as a homing defice  for neutrophils, basophils and T-cells.

·    Tumor Necrosis Factor (TNF)  comes in two flavors: alpha and beta. TNF-alpha is a major immune response-- modifying cytokine produced primarily by activated macrophages. TNF-alpha increases cellular responsiveness to growth factors and induces signaling pathways that lead to proliferation. TNF-beta, produced by cytotoxic T-cells,  is characterized by its ability to kill a number of different cell types and induce other to differentiate into other forms which result in their death.

·    Interferons Interferons are predominantly responsible for the antiviral activities of the interferons.  .

·    Erythropoietin (Epo)  Epo is synthesized by the kidney and   stimulates the proliferation and differentiation of immature red blood cells. When patients suffering from anemia due to kidney failure or chemotherapy are given Epo, the result is a rapid and significant increase in red blood cell count.it 

·    Colony Stimulating Factors (CSFs)   stimulate the proliferation of specific  cells of the bone marrow in adults. Granulocyte-CSF (G-CSF) is specific for its effects on cells of the granulocyte lineage. Macrophage-CSF (M-CSF) is specific for cells of the macrophage lineage  Epo is also considered a CSF as well as a growth factor, since it stimulates the proliferation of erythrocyte colony-forming units. IL-3 (secreted primarily from T-cells) is also known as multi-CSF, since it stimulates stem cells to produce all forms of hematopoietic cells.

The term ‘humoral immunity’ refers to any  soluble factor found in the blood or lymph that contributes to host protection. In reality most of the time, humoral  immunity is describing the role of antibodies, specialized molecules which can attach to antigens. However, there are several other important molecules that are part of this response that are worthy of note, especially the acute phase proteins, a group of plasma proteins, many of which are produced by the liver, whose concentrations increase several-fold during an inflammatory response. Specialized molecules, called interleukins and other cytokines act in many ways like hormones, to stimulate growth and proliferation of these cells in immune organs such as the thymus and bone marrow.

B-lymphocytes: The weapons factory

B-cells are found in follicles of  lymphoid tissues. Though not as numerous as T-cells (B-cells only 10% to 20% of all lymphocytes) B-cells have a critical function: They are the antibody manufacturers. When an  antigen is presented  by the T-cell to a specific B-cell, it enlarges (blast  transformation) and rapidly reproduces , producing clones of identical daughter lymphocytes or plasma cells. Because of this rapid rise in the number of essentially identical cells, B cells can produce large amounts of  a specific antibody to the antigen. In order to appreciate what makes a B cell so special, let’s take a look at what they make.

Antibodies and antigens:  The ammunition

To understand what an antibody is, we must first understand the significance of the word ‘antigen,’ which is easy, since basically anything that causes an immune response is called an antigen. An antigen may be harmless, such as grass pollen, or harmful, such as the flu virus. Disease-causing antigens are called pathogens. The immune system is designed to protect the body from pathogens. Thus, anything that induces a subsequent immune response, as evidenced by the activation and proliferation of B and/or T lymphocytes, is referred to as an antigen.

The important thing to remember about antigens is that they induce antibodies, specialized molecules manufactured by the immune system to tag and destroy anything the immune system considers ‘non-self.’ Antibody either destroys the antigen directly, or coats it so that phagocytic cells (neutrophils  and monocytes) can ingest and destroy the particle or invader. Virtually all proteins are anitgenic. Carbohydrates (usually polysaccharides) are potentially very immunogenic. Polysaccharides that are part of complex molecules (like cell  surface glycoproteins) elicit an immune response directed  specifically against the polysaccharide moiety.  An example are the blood type antigens, which derive their immunologic specificity from the polysaccharides on the surface of  the red blood cells and intestinal lining.

While it should be obvious to almost everyone (though apparently not many health authorities, many of who think we have antibodies to other blood types simply to complicate their  transfusions)  that  the antibodies we make to other blood types are not really being made to another human being’s blood, but rather as a reaction to the innumerous microbes found in the environment which also possess these very same antigens.

There are four principal classes of antibodies, each given a particular letter to identify it from the others.

IgG: The ‘Smart Bomb’

When most people think about an antibody, the one they most commonly envision is IgG, which  is the most abundant form (class) of antibody in the blood.  IgG antibodies are considered the long-term or memory antibodies. For example, once we have been exposed to the measles virus, our body fights off the original infection over time, and further re-infection is prevented because the B-lymphocytes now have a memory of the original measles virus antigen, and have flexed their muscles a bit. For now on, your blood stream contains traces of anti-measles IgG antibody which serves to protect against re-infection.

IgG antibodies do not themselves kill invaders. Rather, they attach to the virus or bacteria and ‘tag’ it so as to give notice to the other circulating cells of the immune system (such as cytoxic T cells or macrophages) that there is an unwelcome guest in the body.

Structurally, it can be useful for use to imagine an IgG antibody as an adjustable monkey wrench. A monkey wrench is comprised of a variable portion (the jaws) and a constant portion (the handle). The benefit of an adjustable wrench is that you can vary the size of the gap between the two jaws of the wrench to accommodate a wide variety of different nut sizes. Like our money wrench, IgG is comprised of two portions, not surprisingly called the ‘variable’ and ‘constant’ regions. The variable region is adjusted to fit the particular shape of the antigen, and the constant portion (like our wrench handle) remains pretty much the same. B-lymphocytes vary the gap by rearranging different molecules to fit the shape of the antigen. Other cells attracted to the antibody (now attached to the invader) recognize the handle or constant portion of the antibody, and can attach to it.

IgM: The deadly snowflake

IgM accounts for about 10% of the total antibody pool in the body and is the  predominant antibody of the early immune response. IgM is the first antibody to be produced in response to infection since it does not require "class switch" to another antibody class. IgM  is the only class produced by the fetus.

It is also the largest of the antibodies. IgM binds to antigens on the surface of a bacteria like a spider. Because of its shape and size, IgM is particularly good at activating complement and causing agglutination.  It is the only antibody type which is capable of destroying antigen-containing cells without the assistance any other cells of the immune system. By far the greater majority of the antibodies we make to an opposing blood type (isoagglutinins) are IgM class antibodies.

IgM exists in its inert form looking much like a two-dimensional snowflake. When it attaches to a foreign cell or other antigen, it now assumes a three dimensional shape which resembles a crab. After attaching, IgM molecules can interlock, forming lattices, which cause the antigens to agglutinate. Therefore, IgM is especially well suited for the agglutination of microbes.  Because of this IgM antibodies are often called ‘isoagglutinins’ which are the naturally occurring IgM antibodies against the red blood cell ABO antigens. Since they can agglutinate cells containing foreign antigens, IgM antibodies possess many of the same characteristics of the lectins.

IgA: The rampant

IgA class antibodies are not found in very high concentrations in the blood. Rather, it is found very commonly on the mucosal surfaces of the body. Typically IgA is bound to the mucus at one end, with the free, or business end, sticking freely out. IgA is found abundantly in saliva, tears and breast milk (especially colostrum) and is the primary defense at mucosal surfaces such as bronchioles of the lungs, the nasal passages, prostate, vagina, and intestine. It normally guards against bacterial and viral infections.

IgA deficiency is the most commonly seen immune deficiency. The deficiency is lifelong and precautions need to be taken to prevent infections.  In general, IgA Deficiency occurs once in every 400 to  2,000 individuals. However, its incidence varies across racial and ethnic lines. Many IgA-deficient patients are healthy, with no more than the usual number of infections.  Others may typically suffer with recurrent ear, sinus, or lung infections that may not respond to  standard courses of antibiotics. These patients can have an increased frequency of allergies, asthma,  chronic diarrhea (often due to parasite), and autoimmune diseases.

  IgE: The antibody of allergy

The word allergy means ‘altered working’. It was coined at the beginning of the 20th century to describe the fact that when dogs were  innoculated with proteins from another animal they had altered reactions when they came into contact with that protein again. These reactions were harmful, and  the dogs died often during the "allergic reaction".

Allergies are the result of your immune system overreacting to normally harmless substances in our environment  These substances have been given the generic name ‘allergen’ which is  a substance that causes no harm to most people  but triggers an array of symptoms in sensitive individuals  ranging from mildly annoying to life-threatening. Common  allergens include dust mites, pollen, foods such as peanuts, wheat and strawberries, and drugs such as penicillin.  Allergies are pervasive in our society. According to the National Institute of Allergy and Infectious Diseases (NIAID), people with allergies spend more than $5 billion annually on  doctors' visits, allergy shots and prescription medications.

An allergic reaction is basically the immune system getting out-of-control. In addition to attacking true enemies such as viruses and bacteria, the immune system of an allergic person also springs to action when an allergen is present. When an allergic person is exposed to an allergen their  B lymphocytes produce a special class of antibodies known as Immunoglobulin E, or IgE. These IgE molecules can readily bind to the allergen that caused their production - they are "specific" for the original allergen. Specific IgE molecules travel through the blood and attach to receptors on the surface of mast cells. Different IgE antibodies are produced  for each type of allergen, whether it's latex, pet dander, oak  pollen or ragweed pollen. Once on the mast cell surface, allergen-specific IgE can remain for weeks or even months, always ready to bind to the original allergen. The next time the allergen enters the body, the allergic cascade begins and eventually results in the release of  histamines from the mast cell. Different chemicals are produced and released depending on the allergen. These chemicals target certain areas of the body, producing a wide  range of symptoms in just minutes or up to one hour. As annoying, or even life-threatening  as they are  allergies do serve something of a purpose - they are an attempt by  the body to wash away the offending allergen.

Symptoms vary in severity and  affect different parts of the body. Some allergens that affect the respiratory system such as pollen, dust mites and mold cause watery eyes and coldlike sneezing, coughing and   postnasal drip. Allergens that affect areas lower in the upper  respiratory system can make it difficult to breathe, and cause  asthma. Food allergens strike the digestive system, causing symptoms such as nausea, vomiting, abdominal cramps and diarrhea.

People seem to inherit allergies, most often from their mothers. At least 3 genes are believed to be responsible for allergy, but only one has been  identified. This gene produces  interleukin 4 (IL-4) a growth factor that is required for production of  IgE. Overproduction of IL-4 leads to more IgE which leads to allergy. One theory postulates that the allergic response is a defensive reaction of the immune system against certain innocuous substances  that the body mistakes for harmful parasites. This is probably true, IgE is found to increase greatly in response to parasite infection. The eosinophils kill parasites (mainly worms) in conjunction with IgE, and one of the classic signs of a child with parasites is an itchy nose and watery eyes –the result of the immune system trying to kill the parasite and meanwhile liberating enough IgE to mimic the symptoms of allergy. Non-Caucasians tend to have higher levelsof IgE than Caucasians, and males tend to have higher levels than females. Like the anti-blood type antibodies, the levels of IgE tend to drop as we age, which perhaps explains why some people grow out of childhood allergies.

Experience shows that there are distinct difference between how the blood types handle allergy

The anti-blood type antibodies

You should have by now some inkling that for many of you there exists one or more blood types that you cannot receive blood from. Your blood  type possesses a blood type antigen for which you carry an opposing antibody. These ‘anti-blood type antibodies’ are often called ‘isohemagglutinins’ because they are made throughout life and are IgM antibodies so they can agglutinate  antigens directly. These are very powerful antibodies!  The best known role of the isohemagglutinins  is  the ‘transfusion reaction’ which occurs when someone is inadvertently given the wrong type blood in a transfusion. This process can be very serious. A person  who receives an incompatible blood transfusion may experience fever, shaking, chills, shortness of breath, hives, and nausea. Shock, kidney failure, or blood coagulation can ensue and rarely even death may occur.

For example:

·    Type A: You have antibodies against blood  type B. You can receive blood from types A and O.  In reality, you consider all things in Nature that are ‘B-like’ foreign.

·    Type B:You carry antibodies against blood  type A. You can receive blood from types  B and O. In reality, you consider all things in Nature that are ‘A-like’ foreign.

·    Type AB: Because both A and B  antigens are present in your red blood cells, you don't carry antibodies for either. You can receive blood from types A, B, AB, and O. Because of this, type AB is often called ‘the universal receiver’

·    Type O: You have antibodies against blood  types A, B and AB. You can only receive type O blood, but you can donate to all  types. Because of this, type O is often referred to as the ‘universal donor’. In reality, you consider all things in Nature that are  either ‘B-like’ or ‘A-like’ foreign.

Apparently, we do not start out in life with antibodies to opposing blood types. We are however genetically programmed to produce them, and within two weeks of life most infants are already becoming sensitized to opposing blood type antigens in their environment.

We manufacture anti-blood type antibodies throughout our life:  A recent study of 644 Taiwanese subjects showed that synthesis of anti-A and anti-B could be demonstrated in most Taiwanese infants by 2-4 months of age, increasing progressively to reach adult levels  at around 1 year of age. Peak levels were reached at between 3-10 years of age and then declined with advancing years, with individuals of 80 years of age and over showing reduced levels similar to those seen in 6- to 12-month-old infants. 

Liu YJ, Chen W, Wu KW, Broadberry RE, Lin M. The development of ABO isohemagglutinins in Taiwanese. Hum Hered 1996 Jul-Aug;46(4):181-4

It has been shown that our levels of the anti-blood type isohemagglutinins is rising: A French study  showed that they are about about 50% higher in children today than was that found in 1929. The authors suggest that this  increased immune reactivity of children observed presently may be due to the increase use of prophylactic vaccinations, and that the levels of anti-blood type antibodies can serve as a pretty good index of antibody immunity, especially in children in the first years of life.

Godzisz J. [Synthesis of natural allohemagglutinins of the ABO system in healthy children aged 3 months to 3 years]. Rev Fr Transfus Immunohematol 1979 Sep;22(4):399-412

  The effect of modern immunizations increasing anti-blood type antibodies is valid. Several common vaccines have been shown to cause inadvertent spikes in anti-blood group antibodies. The best known of these is the common vaccine against Pneumoccal pneumonia (Pneumovax). Several years ago it was noted that the levels of anti-A antibodies increased in individuals who were either blood type O or B when they received this vaccine. It is unclear at this time whether it is the vaccine antigen of a contaminant which produces the spike in anti-A. Several variants of the influenza virus have been shown to increase anti-blood type antibodies, some so consistently that there lack of production in one case history was considered an aberration.

Noel A. Anti-A isoagglutinins and pneumococcal vaccine. Lancet. 1981 Sep 26;2(8248):687-8.

Fagerhol MK, et al.   Lack of ABO isoagglutinin response to influenza A2 infection.  Bibl Haematol. 1965;23:526-8.

Although found predominantly in the blood, many people also have high levels of isohemagglutinins in their saliva and vaginal fluids. One study found that about 36  per cent of the saliva samples had opposing blood group antibodies in it. The amount of antibody appears to vary from one individual to another. Also, different racial groups appear to have different profiles:  Some groups have higher incidences of people with Anti-A in their saliva; others anti-B. This is probably the result of local dietary differences.

Chattopadhyay PK, Ganeson D. Salivary agglutinins in an Indian population. Anthropol Anz 1983 Sep;41(3):221-4

As one of the premiere textbooks of physiology states: “It is difficult to understand how agglutinins are produced in individuals who do not have the respective antigenic substances in their red blood cells. However, small amounts of group A and B antigens are believed to enter the body in the food, in bacteria, or by other means, and these substances presumably initiate the development of anti-A or anti-B agglutinins.”  -Guyton, Textbook of Medical Physiology

A recent short article from the Mayo clinic website does a nice job of summing up why we produce these antibodies:

“S. Breanndan Moore, M.D., a hematologist at  Mayo Clinic, Rochester, Minn., describes the   formation of these naturally occurring  antibodies. "Let's say a child is born with type O red cells. The child will begin forming  antibodies to type A and B red cell antigens as  soon as she starts eating food, because the A    and B antigens are actually found in some  plants. So, as soon as the child starts eating  plant food, she'll be exposed to those antigens   and start making antibodies against them.  Later, if the child is transfused with blood   that's not type O, she'll destroy the new red  blood cells in a process called hemolytic  transfusion reaction." (http://www.mayohealth.org/mayo/9902/htm/bloodtyp.htm)

This is a very provocative statement, no pun intended. Take a moment to contemplate the fact that one of the major immune reactions against non-self, one of the few that is genetically programmed,  is the result of hundred if not thousands of tiny inoculations over the course of a child’s early life with substances in the diet that are chemically identical with getting the wrong blood type in a transfusion!

Strangely enough, it has been reported that a blood type A diabetic receiving a pancreas-spleen transplant from a type O donor went into severe transfusion reaction after high levels of anti-A antibodies began to develop in his bloodstream. Apparently, the spleen went right on thinking that it was type O and continued to manufacture anti-A antibodies.

Salamon DJ, Ramsey G, Nusbacher J, Yang S, Starzl TE, Israel L. Anti-A production by a group O spleen transplanted to a group A recipient. Vox Sang 1985;48(5):309-12

About ten years ago, I measured the levels of these anti-blood type antibodies in several people with a variety of physical ailments. Not surprisingly, in several illnesses characterized by auto-immune dysfunction or excess inflammation, the levels of these antibodies were often found to be sky high. This was especially true in:

·        Rheumatoid arthritis

·        Endometriosis

·        Chronic ear infection

·        Chrohn’s disease of the intestines

·        Asthma

·        Eczema

·        Hives

D’Adamo P. Does ABO bias in innate immunity imply a difference in T-cell response? J. Naturopath. Med.  1991; 2:11-17

Thus it is possible that for many people with these disorders, the up-regulation of their immune response, which is responsible for the inflammatory aspects of the condition, may have had as its cause an initial inoculation by some environmental challenge that possessed the antigenicity of an opposing blood type. Interestingly many of these disorders such as asthma  are also characterized by inappropriate clumping or aggregation of platelets, which are very important with regard to clotting and wound healing.  There is evidence that opposing blood group antibodies may interact with platelets when in high concentration.

Bowles DJ, et al .    Agglutination activity associated with a glycoprotein extract of human platelet plasma membranes: possible involvement in platelet aggregation. FEBS Lett. 1978 Jun 15;90(2):283-5.

Since they serve to protect against infection it is not surprising that the levels of isohemagglutins can increase in times of acute infection. This has been especially noted for individuals who are blood type O, who often dramatic increases in the levels of their anti-A and anti-B antibodies during infections. Paradoxically, in blood type B individuals their levels of anti-A antibodies tend to drop during times of acute infection. A finding that was particularly true of African  type B’s.

Miler JJ, Novotny P, Walker PD, Harris JR, MacLennan IP. Neisseria gonorrhoeae and ABO isohemagglutinins. Infect Immun 1977 Mar;15(3):713-9

Anti-A and anti-B isohemagglutinins levels appear to drop in other illnesses, including  the childhood leukemias.   Compared with healthy children, leukemic children had  lower isohemagglutinin levels  which were also found to be in phase with relapses of their condition. Children who remained in remission had no such depletion of their antibodies.  

Kubikova-Kourilova A, Zahalkova M. Anti-A and anti-B isohemagglutinins in the course of children's leukemias. Neoplasma 1978;25(4):439-44

A complete lack of either anti-A or anti-B was noted in a blood type O patient during an acute crisis of their chronic leukemia.

Ogata H, Hasegawa S. Undetectable ABO isoagglutinin in a patient with chronic myelocytic leukemia. Transfusion 1977 Nov-Dec;17(6):651-4

In adult blood type B lymphoma patients it has been reported that the development of an anti-B antibody can occur, although this would appear to violate all inherent rules of the immune system which mandate that one does not make antibodies to one’s basic tissue antigens, a phenomena termed ‘Horror Autotoxicus.’ Apparently, this can occur as a result of the lymphoma mutating bone marrow cells to sufficiently ‘un-repress’ this control.

Itoh Y, Matsuzawa S. Anti-A-like and anti-B-like cold auto-hemagglutinins in a patient with malignant lymphoma and healthy individuals. Nippon Hoigaku Zasshi 1989 Aug;43(4):332-6

This phenomena (blood type B making an anti-B antibody) was also noted in the blood of two patients who presented with fever and hemolytic anemia. It appeared transiently and was shown to be and IgM antibody . 

Atichartakarn V, Chiewsilp P, Ratanasirivanich P, Stabunswadgan S Autoimmune hemolytic anemia due to anti B autoantibody. Vox Sang 1985;49(4):301-3

In patients with Hodgkin’s Disease, radiation therapy  results in a highly significant fall in the isohemagglutinin levels.

Krusmann W, Slanina J, Wannenmacher M, Nolte I. [Changes in isoagglutinin titers after high-voltage therapy with the large-field technic in Hodgkin's disease patients]. Strahlenther Onkol 1988 Feb;164(2):79-84

A dysfunction in the manufacture of anti-A antibodies has been speculated as a reason  that  persistent and recurrent urinary tract infections are more common in women who are blood type B, non-secretors than in any other group. Gonorrhea, one of the most common sexually transmitted diseases and one with a proclivity for people who are blood type B  has an easier time infecting type B’s when their levels of anti-A are low. Apparently, the anti-A antibody helps the monocytes of the type B immune system to adhere to the gonorrhea bacteria better,

Blackwell CC, et al  ABO blood group and susceptibility to urinary tract infection . J Clin Lab Immunol. 1984 Dec;15(4):191-4.

Kinane DF, Blackwell CC, Weir DM, Winstanley FP, Elton RA ABO blood groups and susceptibility to gonococcal infection. III. Role of isohemagglutinins in increased association of Neisseria gonorrhoeae to monocytes from blood group B individuals. J Clin Lab Immunol 1983 Oct;12(2):83-6

Complement: Chemical weapons of the immune system

Though many of the defense mechanisms that are part of our normal immune response are the result of specific cells, such as lymphocytes or neutrophils, there is one very important chemical mechanism without which neither the cellular or humoral part of our defenses would work. One of the most important is a cascade of enzymes made by the liver The term "complement" was coined by Paul Ehrlich to describe the activity in serum which could "complement" the ability of specific antibodies to cause death of bacteria. 

Complement, as we will see, is not always so complementary, especially if you are a bacteria.

It can be easy to visualize complement as a series of chemicals held in a sort of ‘suspended animation’ in the serum of our blood. If a series of provocations occurs, complement begins to appear, activated by a series of enzymes that act in a cascade. This cascade is much like a phone tree that parents might use to alert each other of a cancelled school day. If Ms. Smith talks to the school and finds out that school is cancelled, she might then called Ms. Brown and Mr. Jones. They in turn would each call two other parents, and so on. Complement works the same way. A foreign antigen, or the attachment of an antibody, activates the first enzyme in the complement cascade, which activates the next, and next –each amplifying the effect of the previous. The final product is the liberation of a very nasty series of enzymes. 

·    Controlling inflammation through immune garbage removal. Although the complement system is very much involved in killing things, one of its other major function is the removal of immune complexes, the insoluble gunk that results from the interaction of an antibody with its antigen. When an antibody attaches to a foreign antigen the resultant combination very often comes out of solution, or precipitates. Much like sugar crystals will precipitate on a string of thread to make rock candy. These precipitates are called immune complexes.  Immune complexes can cause problems if they build up in the blood or tissues;  part of the job of complement is to help clear them and make them soluble, which allows them to bind to red blood cells, which then pass them on to scavenger cells for their ultimate removal. In several auto immune diseases, including  Lupus, it was found that complement deficiencies can predispose to developing the disease the build up of immune complexes  play a role in auto-immunity.

·    Coating bad guys so the good guys can see them. Some complement proteins can coat the microorganism to allow its ingestion by white blood cells (a process called opsonization). Many white blood cells have selctins for certain complement proteins on their surfaces, such as neutrophils, monocytes and macrophages.  When one of the complement proteins binds to a bacteria , these white blood cells can now bind  to it as well.

·    Killing things single handed. Still others  go ahead and just kill the invader itself, by attaching to its surface and drilling holes into it. This is done by attacking the membrane of the bacteria through the production of something called the ‘Membrane Attack Complex’ in essence a molecular ‘tube’ which is assembled through  the surface of the bacteria, causing it to deflate, or lyse.

·    Acting as a homing beam. Others attach to the interloper and acting like a homing beam to other cells of the immune system (like Killer Cells) On B lymphocyte cells several complement proteins interact with immune complexes containing complement components and activate, producing antibodies to the foreign substance.

·    Controlling Inflammation. Complement activation results in the production of lots of pro-inflammatory  chemicals. One of the more potent  complement proteins (C5a)  helps to localize the elements of the inflammatory   response to the site of inflammation by increasing the expression of adhesion molecules on leukocytes and the vascular endothelium.   It  causes neutrophils to degranulate, releasing oxygen free radicals,  prostaglandins and eicosanoids.  It induces fever by stimulating   interleukin  production and it causes mast cells and basophils to degranulate, releasing histamine.  Histamine released from the mast  cells causes the tiny  capillaries in our  body to become more permeable, allowing white blood cells to migrate into the tissues. The effect of complement on inflammation is one of the prime reasons LDL cholesterol is so ‘bad’ for us: LDL cholesterol stimulates complement to increase inflammation at the site of the artery wall, one of the first phases of the damage which will in time become artery plaque.

Bhakdi S, Torzewski M, Klouche M, Hemmes M. Complement and atherogenesis : binding of CRP to degraded, nonoxidized LDL enhances complement activation. Arterioscler Thromb Vasc Biol 1999 Oct;19(10):2348-54

When I was in medical school, we were taught that there were two pathways by which complement can be activated:  

·   The ‘classical’ pathway is triggered primarily by immune complexes containing an antigen and antibody. This is the most common manner in which complement can be activated.

·   The ‘alternative’ pathway is activated principally by repeating polysaccharide  structures such as those found on bacteria. This is probably an older mechanism, which has the advantage of working without the need for outside help by antibodies.

Since the 1980’s immunologists have uncovered a third pathway by which complement can be activated, which has been termed ‘The Lectin Pathway.’

The lectin pathway is similar to the classical pathway except it is initiated by  a  lectin found in our serum called mannan-binding lectin or mannan-binding  protein (MBP).  MBP  binds to the sugar  mannose which is very commonly on the surface of  bacteria. MBP is a member of a special class of lectins, called ‘serum lectins’ that are part of the immune system of many higher animals, including humans. One of the most important functions of MBP, a lectin which may help protect against  repeated ear infection in children.  Not surprisingly, many dietary lectins bind mannose, including the lectin from the common garlic bulb (Allium sativa). Since in this function it is identical to MBP, it is feasible that some of the anti-bacterial effects from garlic consumption may result not from the well-known antibacterial component allicin, but rather from the lectin in the plant stimulating the formation of complement. Leeks, interestingly enough, apparently have the same lectin,  or one very similar, as does garlic.

Dam TK, et al    Garlic (Allium sativum) lectins bind to high mannose oligosaccharide chains. J Biol Chem. 1998 Mar 6;273(10):5528-35.

Aittoniemi J, Rintala E, Miettinen A, Soppi E Serum mannan-binding lectin(MBL) in patients with infection: clinical and laboratory correlates. APMIS 1997 Aug;105(8):617-2

Peumans WJ, Smeets K, Van Nerum K, Van Leuven F, Van Damme EJ Lectin and alliinase are the predominant proteins in nectar from leek (Allium porrum L.) flowers. Planta 1997;201(3):298-302

The actions of Mistletoe (Viscum album), a popular Christmas ornamental and very well-known alternative therapy for certain types of cancer in Europe, are apparently the result of a lectin contained in the plant. Studies have shown that Mistletoe lectin has the effect of increasing complement in addition to several antibodies.