The Immune System in Down's Syndrome
A well-nourished individual with Down's Syndrome, living in the community, in good housing and free of other diseases, will not suffer the rates of infection associated with a defined primary immunodeficiency.
Michael A Kerr (UK)
The immune system is a very complex system of many components which protects us from infection. Without an effective immune system life threatening infection is inevitable. Many of the processes which contribute to immunity also generate inflammation, which plays an important role in limiting infection but can also cause undesirable tissue damage. Many of the symptoms (e.g. rashes, fever etc) that we associate with infection are, in fact, the direct result of an inflammatory process. The inflammation associated with infection usually subsides when the infectious agent is removed.
Clearly, the killing of micro-organisms by the immune system is highly beneficial. There are, however, two situations where the immune system "gets it wrong" and the effects are far from beneficial. The inflammation caused by the immune system trying to destroy the body's own tissues results in auto immune diseases (auto = self) such as rheumatoid arthritis or diabetes. The overreaction to often harmless substances, such as foods or pollen, can result in allergy. Autoimmune diseases and allergy, once induced, do not subside and they have to be controlled by drugs, or in the case of allergy by the avoidance of the cause of the immunological reaction, if it is known.
Many publications have reported abnormalities of the immune system in people with Down's Syndrome, particularly with respect to immunodeficiency and to autoimmunity. There is, however, much disagreement in the literature.
If the immune system is impaired, the resulting immunodeficiency leaves the individual more susceptible to infection, usually recurrent and often of greater severity. Immunodeficiencies can be Primary (due to a genetic deficiency) or Secondary to other processes. Primary immunodeficiencies are very rare and usually very serious; the types of infection suffered are often highly indicative of the nature of the genetic deficiency. Secondary immunodeficiency is very common and can be caused by many things such as malnutrition, stress, drug treatments, other disease processes or indeed other infections. Secondary immunodeficiency can range from the trivial to the very serious and can be transient or long lasting.
Immunodeficiency in Down's Syndrome
Syndrome suffer from an increased incidence of infection implying some genetic immunodeficiency. This has to be kept in proportion and interpreted with caution. A well-nourished individual with Down's Syndrome, living in the community, in good housing and free of other diseases will not suffer the rates of infection associated with a defined primary immunodeficiency.
It has been widely observed that pneumonia, other respiratory infections and gastrointestinal infections are more common in individuals with Down's Syndrome, particularly in very young children. The higher rate of carriage of hepatitis B surface antigen in people with Down's Syndrome is also well documented. However, many of the older studies (particularly those of Hepatitis B) concern people with Down's Syndrome living in institutions where infection is always more prevalent. Hepatitis B carriage is not higher in people with Down's Syndrome living at home.
Respiratory tract infections (viral and bacterial) do appear to be more common in most young people with Down's Syndrome, but it is not clear whether this is due to true immunodeficiency or to other factors such as altered mucus secretion or the structure of the mouth and airways. Most immunodeficiencies are associated with recurrent infection with characteristic organisms which is not the case in Down's Syndrome. An otherwise healthy person with Down's Syndrome will probably not suffer many more serious infections than his or her siblings and will respond to vaccination. As such, children with Down's Syndrome should follow the same protocols of immunisation as other children.
It should be remembered that the presence of trisomy 21 would be expected only to result in (limited) over-expression of proteins coded for on that chromosome. If this has any effect on the health of the individual it may well bear a complex relationship to the observed clinical signs.
Laboratory studies comparing components of the immune system isolated from people with Down's Syndrome and controls have highlighted possible mechanisms for increased rates of infection. However, cynically, it could be said that any study which showed no difference in behaviour between two groups of individuals, would be less likely to be published. Amongst the immunological findings which have been reported in Down's Syndrome are:
- Decreased neutrophil and monocyte function (chemotaxis, phagocytosis and the oxidative burst,) in some studies but not others.
- Normal numbers of neutrophils and monocytes.
- Lowered (in infants) or raised (in adults) immunoglobulin levels, in spite of normal B lymphocyte numbers.
- Raised IgG1 and IgG3 but lowered IgG2 and IgG4 in some Down's Syndrome adults and children.
- Normal or Raised levels of serum IgA and secretory IgA in older Down's Syndrome children and adults.
- Lowered specific antibody responses upon immunisation.
- Normal or raised levels of C3,C4 and C5
Deficiencies in humoral immunity would be expected to result primarily in increased bacterial infection
Altered distribution of T cell populations (e.g. lower CD4/CD8 ratio, more gd T cells ) but normal T cell numbers. Possibly the result of abnormal thymic function.
- Lowered T cell function including the response to specific antigens and some mitogens .
- Altered T cell intracellular signalling.
- Abnormal cytokine production.
- Lowering of some, but not all NK cell functions but increased numbers of NK cells.
Deficiencies in cellular immunity would be expected to result primarily in increased viral infection. The biochemical basis of these deficiencies has not been identified. However, the presence of the gene for a superoxide dismutase (SOD) on chromosome 21 might be expected to adversely affect the functions of phagocytes which use superoxide to kill microorganisms. Since the powerful oxidants destroyed by SOD have been implicated in heart diseases, inflammatory diseases and in cancer, the possession of an excess of this potent anti-oxidant agent might not be all bad news.
The presence of the gene for CD18, one of the subunits of family of leucocyte integrin adhesion molecules important in immunity and in inflammation might be expected to affect leucocyte behaviour in Down's Syndrome. This molecule controls the interaction of all leucocytes with other leucocytes, endothelium, other tissues and with microorganisms. Certainly, the rare genetic deficiency of CD18 causes dramatic immunodeficiency. Over-expresssion of CD18 might be expected to result in more adhesive leucocytes which might have altered tissue distribution or be less active. Some studies have shown that CD18 is not over-expressed in Down's Syndrome.
Other immune system genes coded for on chromosome 21 which so far have not been shown to have effects in Down's Syndrome include several interferon receptors and numerous novel adhesion molecules.
There are a large number of autoimmune diseases which can affect almost any organ in the body, either singly or several at a time. It is well documented that two particular autoimmune diseases are more common in Down's Syndrome; autoimmune thyroid disease and celiac disease.
Autoimmune thyroid disease:
The thyroid is a gland in the neck, which produces hormones controlling metabolism and thus energy production. In autoimmune thyroid diseases the gland is gradually destroyed leading to marked changes in behaviour which is usually associated with lack of energy (hypothyroidism) but sometimes with over-activity (hyperthyroidism). These diseases usually affect middle-aged women. It has been recognised for many years that even young people with Down's Syndrome (male or female) can suffer from thyroid dysfunction, which can often be attributed, particularly in those over eight, to autoimmune thyroid disease. Since the symptoms of thyroid disease share some similarity with those associated with Down's Syndrome, it is often missed. Simple laboratory blood tests (Thyroid Stimulating Hormone, free or total T4) readily detect abnormal thyroid function. In autoimmune thyroiditis, the characteristic autoantibodies, anti-TSH receptor and anti-thyroid peroxidase antibodies (formerly anti-thyroid microsomal antibodies) are also easy to measure. Children and adults with Down's Syndrome should be screened regularly for thyroid function. Thyroid dysfunction is readily corrected by hormone (thyroxine) replacement, taken orally
Cœliac disease is an immunologically mediated intolerance to a group of wheat proteins called gluten (gliadin). This generates an autoimmune disease which damages the absorptive surfaces of the intestine causing the loss of villi leading to malabsorption of nutrients which can result in weight loss, lethargy and anaemia.
Other autoimmune diseases and allergy:
There have been a number of less definitive studies concerning diabetes and less common autoimmune diseases ( hypoparathyroidism, alopecia) which might be more prevalent in people with Down's Syndrome. A gene associated with autoimmune polyglandular syndrome which can cause these diseases is located on chromosome 21. There have been surprisingly few studies of the relative incidence of allergy in Down's Syndrome. It should be remembered that in contrast to infectious disease, the overall incidence of autoimmune disease and allergy, in particular, is increasing dramatically in the developed world.
Leucocytes, are the essential cells of the immune system. There are many different types of leucocytes each playing a specific role in immunity. Perhaps because they are so active, leucocytes are apparently more prone to developing the cellular damage which leads to cancer. Leukemias are one group of malignancies of white cells which, like most cancers, are more common in the elderly. There are many types of leukaemia and at least two are more common in Down's Syndrome. These are acute lymphoblastic leukaemia (ALL) and acute non-lymphoblastic leukaemia (ANLL). The latter is far more common in very young children with Down's Syndrome. The former, which is also more common in Down's Syndrome usually affects children. This is one of the more treatable of leukemias. Interestingly, cancers of solid tissues as opposed to blood cells might be less common in people with Down's Syndrome, possibly the result of increased production of superoxide dismutase.
HOW MEANINGFUL ARE LABORATORY FINDINGS FOR THE ACTUAL HEALTH OF INDIVIDUALS?
Although these differences can be detected in the laboratory, their effects in vivo are not well defined and the increased incidence of infection in people with Down's Syndrome has to be kept in proportion. All individuals differ markedly in their ability to fight different infections and we understand much about the genetic basis of this diversity. The origin of this diversity lies primarily on chromosome 6 and is probably unaffected by Down's Syndrome. It is evident to all that even in an epidemic of, for example, influenza, not all of us will succumb to infection.
Infection does remain the biggest cause of death and illness in the world, usually amongst the very young whose immune system has yet to develop fully and the elderly whose immune systems is becoming less efficient. However, there are huge differences between the developed and the developing world. In the developed world the incidence of most infectious diseases has declined dramatically as a result of good nutrition, housing and healthcare. Clearly any individual's resistance to infection is dramatically affected by their way of life. The relatively small increases in rates of infection of individuals with Down's Syndrome should not be of major concern. The vast majority of infections can be dealt with, using antibiotics if appropriate, in the primary care setting.
Many studies in different countries have shown increased incidence of celiac disease in people with Down's Syndrome. Again, simple blood tests for characteristic antibodies ( IgA anti-gliadin; IgA anti-endomysial antibodies) can be diagnostic, although final proof might require gut biopsy. Cœliac disease is usually corrected by introduction of a gluten-free diet. Patients should receive appropriate education on the use of the wide range of gluten free foods that are available.
This article was first published on the site in 2002.