It is clear that there is an increased incidence of celiac disease in certain families, providing support for the hypothesis that there is a genetic predisposition to the disease. We continue to stress, however, that this predisposition may be insufficient for development of the disease without the intervention of some environmental factor - other than gluten proteins.
Celiac disease occurs in about 14 percent of siblings, 8 percent of parents, and 15 percent of children of celiac patients (Strober 1992). Although dizygotic (fraternal) twins do not show major differences from normal siblings in their tendency to develop celiac disease, monozygotic (identical) twins are about 70 percent concordant for the disease. The fact that 30 percent of the identical twins are discordant, with one having the disease and the other being free of it, is strong support for the necessary role of an environmental factor, such as viral infection (Kagnoff et al. 1984) or some other stressful event.
It was recognized in conjunction with attempts to transplant tissues from one individual to another, that certain protein antigens (human leukocyte antigens, or HLA molecules) had to be matched to avoid rejection of the foreign tissue. These proteins, now often called the proteins of the major histocompatibility complex (MHC proteins, MHC antigens), are coded by a cluster of genes on human chromosome 6. MHC proteins are cell-surface receptors, proteins that bind peptides at specific binding sites for presentation to a receptor site on T cells. The T-cell receptor must interact simultaneously with both the MHC molecule and the peptide presented by the MHC molecule before the presentation is recognized as a signal for the T cell to carry out some other function. An activated T cell might go on, for example, to activate B lymphocytes to produce antibodies, or it must suppress the normal immune response to antigens encountered as part of our food intake (development of oral tolerance). The latter function may be especially important because, presumably, in most people the immune response to gluten peptides has been suppressed, whereas in celiac patients, certain gluten peptides trigger an immune response capable of damaging the small intestine.
The MHC proteins of concern to us here are divided into class I and class II on the basis of a number of distinguishing characteristics, one of which is the type of cell on which they are expressed. Class I antigens appear on most cells, whereas class II antigens are found mainly on cells of the immune system, although class II antigens are expressed on the surfaces of enterocytes as well. The first demonstrations of associations between MHC proteins and celiac disease indicated that a class I antigen, designated HLA-B8, was found in nearly 90 percent of celiac patients but in only about 20 percent of controls (Falchuk, Rogentine, and Strober 1972). This antigen, HLA-8, was the genetic marker that, as was discussed earlier by Simoons, was thought to determine the incidence of celiac disease throughout the world.
However, subsequently it became clear that associations of celiac disease with class II antigens were even stronger than those of the class I antigen HLA-B8. Particularly strong associations have been found for the HLA class II alleles DR3 and DQ2.The association with HLA-B8 apparently resulted from linkage disequilibrium in which certain closely linked genes tend to remain associated during genetic recombinations to a greater extent than would be expected.
The associations of celiac disease with various MHC proteins observed throughout the world are quite complex (see reviews of Kagnoff 1992;Tighe and Ciclitira 1993), but they are sufficiently strong to make it seem likely that class II antigens are directly involved in the mechanisms responsible for tissue damage in celiac disease - possibly by presenting peptides derived from gluten proteins to T cells.
In support of the possibility that gliadin peptide binding by T cells is involved in celiac disease, K. E. A. Lundin and colleagues (1993) have found that T-cell lines derived from intestinal biopsies recognized gliadin peptides, and the cell lines were mainly stimulated by antigen presentation in the context of the DQ heterodimer. In addition, H. A. Gjertson, Lundin, and colleagues (1994) found that a peripheral blood lymphocyte clone from a celiac patient specifically recognized a synthetic peptide corresponding to alpha-gliadin residues 31-47. Further interest in the role of class II MHC proteins derives from studies showing that HLA-DR molecules, which are expressed by enterocytes of normal individuals or of celiac patients on a wheat-free diet (Arnaud-Battandier et al. 1986; Ciclitira et al. 1986), became differentially expressed in the crypt cells of celiac patients (but not in those of normal controls). This occurred when gluten proteins or peptides were added to biopsied tissues in culture that had been obtained from treated patients on a wheat-free diet (Fais et al. 1992).
W. Strober (1992) has pointed out that because discordance for celiac disease is much less common in identical twins than in siblings who have apparently identical complements of histocompatibility antigens (MHC proteins), it seems likely that the difference cannot be explained by an environmental factor because the contribution of environmental effects should have been about the same for the sets of twins and siblings. Strober considers this as strong evidence for a contribution by some non-MHC-defined disease gene. Whether or not this gene turns out to lie outside the MHC complex, celiac disease is likely to have a two-locus basis. D. A. Greenberg, S. E. Hodge, and J. I. Rotter (1982) considered that the available data fit best with a recessive-recessive two-gene model, but studies in the west of Ireland (Hernandez et al. 1991) favored dominance for the gene associated with the HLA locus. Conclusions may be somewhat dependent on the population studied, as many diseases show variation in their genetic basis.
Associated Diseases
Many different diseases have been reported to occur concurrently with celiac disease, including dermatitis herpetiformis, insulin-dependent diabetes, Down syndrome, IgA nephropathy, and epilepsy associated with cerebral calcifications (Bayless, Yardley, and Hendrix 1974; Gobbi et al. 1992; Collin and Maki 1994). In only a few diseases are statistically significant data available for the establishment of an association with celiac disease.
Dermatitis herpetiformis is a disease manifested by a rash with small blisters and IgA deposits even in uninvolved skin (Fry 1992). It is quite strongly associated with celiac disease. Intestinal lesions similar to those encountered in celiac disease are found upon biopsy of about two-thirds of patients with dermatitis herpetiformis, and a gluten-free diet usually improves both the skin rash and the intestinal lesions. Furthermore, even those patients without significant damage to the intestinal epithelium usually have an increased number of intraepithelial lymphocytes, and patients without obvious mucosal damage have developed such damage when their intake of gluten was increased. Nevertheless, malabsorption is much less common in dermatitis herpetiformis than in celiac disease (Kumar 1994). Indeed, the incidence is rather less than that of celiac disease, with dermatitis herpetiformis occurring about half as frequently as celiac disease in Sweden and perhaps one-fifth as frequently in Scotland (Edinburgh).
Insulin-dependent diabetes mellitus also shows a definite association with celiac disease. Between 5 and 10 percent of children with celiac disease have diabetes mellitus, whereas about 1 to 3 percent of children with diabetes mellitus have celiac disease (Visakorpi 1969; Strober 1992). Both celiac disease and insulin-dependent diabetes mellitus share an association with the histocompatibility antigen HLA-DR3 (Maki et al. 1984), and the common MHC gene(s) may predispose individuals carrying them to both conditions.
Down syndrome may be weakly associated with celiac disease. J. Dias and J. Walker-Smith (1988) found an increased incidence of Down syndrome in celiac patients compared with the incidence in the general population. They considered this as supporting evidence for earlier findings (Nowak, Ghisham, and Schulze-Delrieu 1983). M. Castro and colleagues (1993) have confirmed a significant increase in celiac disease among Down syndrome patients and found that antigliadin antibodies provide a useful screening tool to look for celiac disease among these patients. In addition, there are reports that patients with schizophrenia, autism, and IgA nephropathy have apparently benefited by removing wheat (and related harmful grains) from their diets, although such reports are not universally accepted as valid.
There have been extensive attempts to show a correlation between schizophrenia and celiac disease (Dohan 1966,1988; Lorenz 1990), but the results have not been convincing. Evidence for intestinal damage in the group of schizophrenics studied by F. M. Stevens and colleagues (1977) was no greater than that for controls, and there was no significant increase in serum antireticulin antibodies. Both intestinal damage and antireticulin antibodies are usually present in celiac patients taking a normal (wheat-containing) diet. Nevertheless, published reports from physicians indicating that removal of wheat from the diet can produce a marked reduction in psychotic symptoms for some schizophrenics were considered sufficiently convincing by K. Lorenz (1990) to indicate that in at least a subset of schizophrenics, wheat has an adverse effect on the disease. Even in studies where no positive correlation was found, investigators noted that some patients did apparently show considerable improvement on a wheat-free (“gluten-free”) diet (Rice, Ham, and Gore 1978).
Some celiac patients on a gluten-free diet, perhaps about 25 percent (Ansaldi et al. 1988), have indicated that they feel temporary psychological disturbance upon eating wheat, including symptoms such as irritability, hostility, depression, or a general feeling of mental unease. Although such symptoms may be “normal” in the face of physiological changes produced by eating wheat, investigation of a connection between such responses in celiac patients and the effects of wheat in the diet of carefully selected schizophrenics might be worthwhile. Again, even if wheat in the diet does adversely affect the course of schizophrenia, the mechanisms involved may be quite different from those involved in producing intestinal damage in celiac disease.
The role of wheat in autism is also controversial, but development of the hypothesis that wheat and casein exacerbate the symptoms of autistic patients parallels that for schizophrenia. The hypothesis is based so far on studies that indicate value for a wheat-free diet in improving behavior of patients with autism (Reichelt et al. 1991), although these studies are not well controlled because of the difficulties in carrying them out with patients who may not be able to supply informed consent. It has been discovered that amino acid sequences found in the primary structures of wheat gliadin proteins and casein proteins are similar to those of endorphins and other neuroactive peptides termed exorphins (Zioudrou, Streaty, and Klee 1979). It has been proposed that these, along with other neuroactive peptides from wheat, are responsible for the exacerbation of symptoms claimed for schizophrenic patients on a normal, wheat-containing diet (Zioudrou et al. 1979; Dohan 1988). This working hypothesis is also favored by some researchers investigating the possibility that wheat and casein proteins in the diet exacerbate symptoms in autistic patients (Reichelt et al. 1991). According to the hypothesis, food-protein-derived neuroactive peptides pass through the wall of the intestine and also pass the blood-brain barrier to affect brain function. This results in a variety of abnormal behaviors.
Abnormal peptide patterns appear in the urine of autistic subjects and schizophrenics (Cade et al. 1990; Shattock et al. 1990; Reichelt et al. 1991), and the hypothesis has been put forward that these abnormal patterns reflect to some extent the abnormal absorption and then excretion of exorphin peptides derived from wheat or milk proteins in the diet. This implies either excessive passage through the intestinal wall and/or a failure in some other way to process these peptides into harmless forms. However, that these abnormal urine peptide patterns truly represent excretion of peptides of dietary origin does not seem to have been proved.
IgA nephropathy is a kidney disease characterized by protein and blood in the urine and IgA deposits in the kidney (Stevens, Lavelle, et al. 1988). Although the severity is variable, the disease can lead to chronic renal failure. Reports of concurrence with celiac disease, the presence of circulating IgA antibodies to gluten proteins, and patient improvement (even with nonceliac patients) on a gluten-free diet have led to speculation that there may be a connection between the two diseases (Coppo et al. 1986; Sategna-Guidetti et al. 1992). It has been suggested that IgA nephropathy might be similar to dermatitis herpetiformis, with the main difference being that IgA deposits form in the kidney rather than in the skin. However, the evidence indicates that epithelial damage is uncommon in IgA nephropathy, although the activities of marker enzymes in the brush border were significantly lower (Stevens, Lavelle, 1988). Gliadin proteins or peptides have been found in complex with the IgA deposits in IgA nephropathy (Russel et al. 1986), and similar associations should be sought in dermatitis herpetiformis.
Celiac patients have been found to be at increased risk of developing certain types of cancer (Holmes et al. 1989; Logan et al. 1989; Holmes and Thompson 1992), especially small intestinal lymphoma. Nonetheless, the absolute risk of a celiac patient dying from this cancer is small because the incidence in the normal population is quite low.
G. K. T. Holmes and colleagues (1989) found in a study of 210 patients that those who had been on a strict gluten-free diet for more than 5 years did not have significantly increased risk of developing lymphoma. But the risk of developing lymphoma was reported to be high (1 in 10) for celiac patients who were diagnosed late in life (over the age of 50). The investigators did not discuss what constituted a “strict gluten-free diet,” and J. A. Campbell (1992) has pointed out that it would not have been unusual for patients who thought themselves to be on a strict gluten-free diet to be using products containing wheat starch, which has a small amount of gluten in it. It seems prudent for celiac patients to follow a strict gluten-free diet as recommended by Holmes and colleagues (1989), but whether traces of gluten in the diet, such as might result from use of wheat-starch products, contribute to the development of malignancies late in life does not appear to have been established.
World History
