Immunopathology

IgA deficiency

Selective deficiency of IgA (or P2A or y1A according to previous terminology) was described by Giedion and Scheidegger (1957), Fudenberg et al. (1962), and West et al. (1962). Interestingly, these initial reports contained descriptions of patients whose symptoms presaged the clinical profiles of patients with IgA deficiency as defined in later, more extensive studies of the condition. Some of the patients, for instance, had respiratory infections and thus predicted the major clinical manifestation of IgA deficiency, that is, chronic upper and lower respiratory infections leading in the untreated state to bronchiectasis and respiratory failure. In addition, one patient had steatorrhea and malabsorption and was therefore representative of another symptom complex in IgA deficiency, a non-gluten-sensitive sprue-like syndrome marked by villous atrophy, malabsorption, and at times, intestinal nodular lymphoid hyperplasia. The origin of this symptom complex, initially described in depth by Crabbé and Heremans (1966), is still poorly understood, although most students of IgA deficiency consider it to be an autoimmune manifestation of the disease (McCarthy et al., 1978). On this basis, it must be differentiated from gastrointestinal problems due to infections of the gastrointestinal tract such as giardia or salmonella infection, which have been shown to occur more frequently in IgA deficiency than in normals by Ammann and Hong (1971). Finally, one patient in the West series had a lupus-like syndrome and was thus indicative of the rather strong association of IgA deficiency with autoimmunity, as later shown by the increased incidence of "silent" IgA deficiency in autoimmune diseases and the increased incidence of antibodies against self-proteins or food proteins and frank autoimmunity in IgA-deficient patients themselves (Buckley and Dees, 1969; Ammann and Hong, 1971; Cassidy et al., 1973). The basis of this association was later investigated by Cunningham-Rundles et al. (1978), who showed that IgA-deficient patients absorb an increased amount of intact macromolecules from the food into the bloodstream and, in addition, manifest high levels of circulating antigen-antibody complexes following food ingestion that presumably arise as a result of prior antibody responses to the absorbed food protein. In addition, these investigators showed that the presence of absorbed food molecules and antigen-antibody complexes in the circulation correlated with the presence of autoantibodies or autoimmune disease. Thus, they postulated that in the absence of IgA, the gastrointestinal tract manifests reduced barrier function and permits entry of macromolecules, some of which cross-react with self-antigen and give rise to autoantibody responses (Cunningham-Rundles et al., 1981).

Another early milestone in the history of IgA deficiency was the discovery in 1964 by Rockey et al. (1964) that IgA deficiency can occur in ostensibly healthy individuals. This finding was later expanded by epidemiologic studies of blood bank donors, which established that IgA deficiency is mainly a "submerged" immunodeficiency occurring in 1/300-1/2000 individuals in various Caucasian populations (Hanson et al., 1983).The existence of such seemingly silent IgA deficiency has prompted studies to determine the factors that result in increased susceptibility to infection. One factor, first identified by Oxelius et al. (1981), relates to the finding that a subset of patients with IgA deficiency also have IgG subclass deficiency, and thus are at further risk for infection. Indeed, as subsequently shown by Bjorkander et al. (1985), many, but not all, patients with associated IgG subclass deficiency had a greater frequency of infections than patients with IgA deficiency alone. Another factor, identified by Mellander et al. (1986), relates to the ability of IgA-deficient patients to manifest compensatory IgM or IgG antibody responses that then presumably provide sufficient protection at mucosal surfaces to prevent infections; it should be noted here that in humans, IgM like IgA can be transported to the mucosal surface via the polymeric Ig receptor. Finally, the level of IgA produced in patients may be a factor in the occurrence of infection. Thus, patients whose immune systems produce virtually no IgA may be at greater risk than those that produce reduced amounts of IgA. Two caveats concerning silent IgA deficiency are in order. First, as emphasized by Cunningham-Rundles et al. (1980), such unidentified immunodeficiency may in fact be a risk factor for gastrointestinal neoplasia or, as mentioned earlier, autoimmunity. Second, although silent IgA deficiency may be silent in the relatively clean environments of Western, industrialized countries, it may lead to disease in less developed countries that have environments more closely approximating those that led to the evolution of the immune system.

The finding that some patients with IgA deficiency do produce some IgA and thus have what might be called a partial IgA deficiency relates to the important studies of Savilahti and Pelkonen (1979) showing that a sizable group of IgA-deficient patients, mostly those who have partial IgA deficiency, exhibit transient IgA deficiency that eventually reverts to normal.The causes of such transient deficiency are presently unclear. Among the possibilities that have been suggested is exposure to certain viruses and drugs (particularly anticonvulsants) as well as certain insults to the immune system such as graft-versus host disease, all of which have been associated with IgA deficiency in one way or another (Savilahti and Pelkonen, 1979; Elfenbein et al., 1976). Whether such transient IgA deficiency is qualitatively different from complete IgA deficiency remains to be explored, as does the question of whether all forms of IgA deficiency require an environmental trigger.

Yet another observation concerning IgA deficiency that was made in the early years following its discovery was that of LaPlane et al. (1962) showing that the deficiency occurs in relatives of patients with common variable immunodeficiency (CVI). This observation was the first to suggest that IgA deficiency and CVI are related diseases and to suggest that these immunodeficiencies have a common genetic basis. These possibilities were later put on a firmer footing by the discovery that the two diseases share a common set of HLA haplotypes and that IgA deficiency occasionally evolves into frank panhypogammaglobulinemia (see Chapter 64). In addition, it eventually became apparent that the immuno-logic abnormalities found in IgA deficiency and CVI were fundamentally similar and thus the two deficiencies represented two ends of the same disease spectrum. As for genetic studies of IgA deficiency (and CVI), these begin with the studies of Koistinen (1975), who noted familial clustering of IgA deficiency and the studies of Van Thiel et al. (1977) showing the occurrence of kindreds with IgA deficiency and various autoimmune diseases. Ambrus et al. (1977) showed that IgA deficiency was associated with HLA-B8 and thus ushered in a series of studies of MHC genes in IgA deficiency and CVI.

The previous considerations bring us to studies of the immunopathogenesis of IgA deficiency (and CVI). In the late 1970s and throughout the 1980s, evidence was accumulated that established that although IgA deficiency (and CVI) may sometimes be associated with class-specific suppressor T cells, the more constant and more basic deficit resides in the B cells. In particular, it was shown by Mitsuya et al. (1981) and Pereira et al. (1982) that IgA B cells in IgA deficiency (and all B cells in CVI) manifest defective class switching and terminal differentiation. Interestingly, this defect in patients with CVI appears to be hierarchical in the sense that upon in vitro stimulation, IgA differentiation is most affected, IgG differentiation is next most affected, and IgM differentiation is least affected.

Renal diseases

Mucosal infections of the respiratory tract and diseases of the gastrointestinal tract or liver may result in the alteration of IgA metabolism and the deposition of IgA1 in the glomerular mesangium and skin. Berger and Hinglais (1968) and Berger (1969) described a new form of glomeru-lonephritis characterized by prominent codeposits of IgA and IgG in the glomerular mesangium. The disease, now termed IgA nephropathy, or according to its discoverer, Berger's disease, is the most common cause of glomeru-lonephritis in the world.

Subsequent studies indicated that the mesangial deposition of IgA1 also may be present in other diseases including Henoch-Schonlein purpura (HSP), systemic lupus erythe-matosus, dermatitis herpetiformis, alcoholic liver cirrhosis, and inflammatory bowel disease. Although HSP in children was first described by Heberden (1801), and then by Schonlein (1837), and Henoch (1874), its relationship to IgA nephropathy was elucidated relatively recently. Interestingly, based on the careful review of historical records of the symptoms and duration of the disease, Davies (1991) speculated that the kidney failure and ultimate death of W. A. Mozart was due to HSP.

Gluten-sensitive enteropathy (GSE)-celiac disease and celiac sprue

The discovery of GSE is credited to W. K. Dicke, a Dutch pediatrician, who noted during the mid-1930s that one of his patients repeatedly developed diarrhea and rash soon after the ingestion of bread (Dicke, 1941). Notwithstanding the fact that, in retrospect, the clinical syndrome in this patient is better classified as allergy to wheat protein rather than GSE (which is a nonallergic immunologic hypersensitivity and does not result in immediate symptoms), Dicke generalized this observation to a larger group of children with chronic diarrhea and wasting who probably did have GSE. On this basis, in a 1940 meeting of the Dutch Pediatric Society, he proposed a wheat-free diet for children with GSE (then called Gee-Herter syndrome). There is a persistent anecdote that Dicke subsequently became convinced of his theory in the early 1940s during the German occupation of Holland when he noted that the children with GSE actually improved in spite of the general food shortage (which of course included a wheat shortage) and suffered relapses at one point when wheat was air-lifted into Holland by the Allies (Smits, 1989). Finally, in the late 1940s, Dicke teamed up with several Dutch scientists, particularly J. H. Van de Kamer, who had devised a method of measuring fat excretion in the stool to formally show that feeding of certain cereal grains to patients with GSE led to increased fat excretion (i.e., fat malabsorption) (Van de Kamer et al., 1953). This result, published as a Ph.D. thesis by Dicke in 1950, was rapidly reproduced in other parts of Europe and GSE was thus uniquely defined as a diarrheal syndrome due to cereal grain protein hypersensitivity (Dicke, 1950).

In the approximately 50 years that have elapsed since this singular discovery, there have been many important additional landmarks in the study of GSE. In the 1950s, it was shown that GSE is characterized by the presence of villous atrophy and that the loss of absorptive surface that results from such atrophy is responsible for the main clinical manifestation of the disease—malabsorption and nutrient deficiency (Paulley, 1954; Shiner, 1960). This discovery also enabled clinicians in the 1960s to link the skin disease, dermatitis herpetiformis, to GSE because patients with dermatitis herpetiformis could also be shown to have various degrees of villous atrophy and to have amelioration of disease with a gluten-free diet (Shuster et al., 1968).The existence of two clinical forms of gluten sensitivity led to the increasing use of the term gluten-sensitive enteropathy rather than celiac disease as the more inclusive name for the disease. Finally, during this early period of the study of GSE, it was also established that the offending protein in gluten causing GSE was the wheat prolamin known as gliadin; as shown later, similar components of rye and oat grains also cause GSE (Dicke et al., 1950).

In the 1960s and early 1970s, the first evidence that GSE was associated with gluten-specific immune dysfunction appeared in studies showing that patient mucosal tissue displayed evidence of increased immunologic activity, including increased numbers of plasma cells in lamina propria and increased intraepithelial cells (Eidelman et al., 1966; Ferguson and Murray 1971). In addition, it was shown that high serum IgA levels prevalent in GSE tend to fall after the institution of a gluten-free diet (Asquith et al., 1969), and feeding of gluten to patients with quiescent disease leads to a prompt increase in IgA and IgM synthesis, some of which is gluten specific (Loeb et al., 1971). Finally, the first evidence that T-cell immunity might be involved in GSE appeared with a report from Ferguson et al. (1975) showing that lymphocytes from patients produce a cytokine upon exposure to gluten (migration-inhibition factor). At this point, strong evidence that the disease was in fact due to an immunologic abnormality was then provided by Falchuk et al. (1974) and Katz et al. (1976), who used organ culture techniques to show that gliadin was not directly toxic to patient tissue, but instead required the stimulation of an "endogenous mechanism," which results in the secretion of soluble mediators of villous atrophy and which is inhibitable by steroids. The "endogenous mechanism" was at that time assumed to be and was later proven to be an immunologic reaction resulting in the production of IFN-y (Przemioslo et al., 1995).

These developments were now expanded, beginning in the early 1970s and extending into the 1980s, by the discovery that GSE is strongly associated with a particular set of MHC genes. The initial finding here was made by Falchuk et al. (1972), who showed that GSE is associated with the MHC class I gene encoding HLA-B8. This observation was later followed by those of Keuning et al. (1976) and Tosi et al. (1983), who demonstrated that GSE was associated with the MHC class II genes encoding HLA-DR3, HLA-DR7, and most importantly, HLA-DQ2.

Inflammatory bowel disease

The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are commonly thought to have been "discovered" relatively recently, that is, in the last 100 years. Review of the historical record, however, quickly discloses that although the prevalence of these diseases may have vastly increased during this period, the first cases were recognized hundreds of years ago and numerous cases were described in the British medical literature in the last half of the 19th century. Thus, as far as ulcerative colitis is concerned, the first clearly reported case can be traced back to Wilks and Moxon (1875), who described a young woman with ulcerations involving the entire colon and who ultimately died of the complications of bloody diarrhea. Over the next 25-40 years hundreds of cases of ulcerative diseases of the colon were reported, not only in Britain, but also in other European countries and ulcerative colitis was a major gastrointestinal disease at the time of the Congress of Medicine held in Paris in 1913. Similarly, with respect to Crohn's disease, the first case was reported by Wilks (1859) who described a 42-year-old woman with inflammation of both the colon and terminal ileum who died after several months with diarrhea and fever; this patient was initially said to have ulcerative colitis, but on reevaluation of the findings much later was found to have had Crohn's disease. Similar cases were reported by Fenwick (1889) and Dalziel (1913) on 13 patients with more or less classic findings of Crohn's disease, which were attributed to a mycobacterial agent other than Mycobacterium tuberculosis (Tietze, 1920; Moschcowitz and Wilensky, 1923). In the ensuing 20 years, numerous instances of gastrointestinal disease resembling Crohn's disease were reported that finally crystallized the idea that Crohn's disease is a separate and unique disease entity. In 1932, two young physicians, an internist and a surgeon, presented findings related to what they proposed was a new clinical and pathologic entity: terminal ileitis with granulo-matous inflammation. Ginzburg and Oppenheimer (1932) reported on 51 cases of granulomatous inflammation of the bowel that were not tuberculous, amebic, or syphilitic. They proposed six categories, including one with isolated terminal ileitis characterized by fissuring, longitudinal ulcers, granu-lomatous inflammation, stenotic bowel, and the propensity to fistulize. This series was published in 1932 in the Transactions of the American Gastroenterological Association with only Ginzburg and Oppenheimer as authors. One month later, Burrill B. Crohn presented 14 cases of pure ileitis and published a landmark paper describing the clinical, pathologic, radiographic, and therapeutic features of the disease. Cases from both studies were from the service of Dr. A. A. Berg, a noted Mount Sinai surgeon (Chief of Service). Dr. Crohn's paper, published in the Journal of the American Medical Association, received the critical acclaim and notice, hence the disease designation Crohn's disease. The initial presentation by Dr. Ginzburg did not include Crohn's name and this has led to some debate regarding the appropriate naming of the disease. The Scots refer to terminal ileitis as Dalziel's disease, the world as Crohn's disease, and Ginzburg, until his death in the 1990s, as Ginzburg's disease. The Crohn et al. (1932) publication was able to establish a new disease entity and ultimately to provide its eponymous name, not because it contained a more extensive series of cases of chronic intestinal inflammation than earlier reports, but rather because it provided specific evidence that the inflammation was not due to a known infectious agent, particularly M. tuberculosis, and was therefore a new type of inflammatory bowel disease. Thus, it justifiably stands as a landmark in the history of gastrointestinal disease and mucosal immunopathology.

More complete clinical and pathologic characterization of ulcerative colitis and Crohn's disease followed the initial definition of these diseases as outlined previously. Ulcerative colitis was characterized as a relatively superficial disease usually beginning in the rectum and then extending proxi-mally to involve the descending colon in some patients and the entire colon in others; in addition, the characteristic microscopic findings of the disease were identified including epithelial cell hyperplasia and goblet cell depletion, the presence of crypt abscesses, and a mixed lamina propria infiltrate of lymphocytes and eosinophils (Warren and Sommers, 1954). In contrast, Crohn's disease was defined by the presence of focal lesions of the small intestine, most commonly involving the terminal ileum but also frequently involving the ascending colon; furthermore, the lesions themselves were shown to be characterized by transmural thickening, luminal narrowing, fistula formation, and fibrosis (Warren and Sommers, 1948). Finally, Crohn's disease, on microscopic examination, was shown to be a granulomatous inflammation sometimes associated with the presence of giant cells, and although crypt abscesses were also present in Crohn's inflammation, overall granulocytic infiltration was far less prominent than in ulcerative colitis (Warren and Sommers, 1948; Rappaport et al., 1951). On the basis of these distinctive morphologic features, ulcerative colitis and Crohn's disease could clearly be defined as different pathologic entities. Nevertheless, they remained grouped as members of the inflammatory bowel disease spectrum because they both were idiopathic inflammations of the intestine without an obvious infectious etiology. In addition, they were found to be genetically related diseases in that patients with one of the forms of inflammatory bowel disease frequently had family members with the other form (Jack-man and Bargen, 1942).

For many years, the cause of both ulcerative colitis and Crohn's disease was assumed to be infectious in nature and one after another candidate organism was championed as the causative agent. In the 1920s, for instance, diplostreptococci, organisms ordinarily found in the oral cavity, were considered the cause of ulcerative colitis, and in the ensuing decades, Pseudomonas aeruginosa, E. coli, Entamoeba histolyt-

ica, and Chlamydiae were likewise considered. Later in the 1950s and 1960s, these bacterial and parasitic candidate organisms lost favor—instead, various viruses were believed to be the etiologic agent. A similar pattern emerged for Crohn's disease beginning in the era before Crohn's report with the assumption that the disease was due to a mycobacterial infection; it was in fact the exclusion of mycobacterial infection by animal inoculation, syphilis by serologic testing, and actinomycosis by histologic findings, that allowed Crohn's disease to emerge as a separate entity (Crohn et al., 1932). This initial exclusion of an infectious etiology, however, did not stop the search for an infectious agent and in the period extending from 1952 to 1985, numerous organisms were proposed as causes of Crohn's disease including various bacterial, chlamydial, and viral organisms. The last enjoyed a particular vogue throughout the 1970s and into the 1980s, but was all but eliminated as a possibility by the inability to culture viral organisms from lesions (Phillpots et al., 1980). Of note, interest in the mycobacterial etiology of Crohn's disease resurfaced in the late 1970s and 1980s with the emergence of evidence that the disease was caused by an atypical cell wall-deficient mycobacterial species (Chiodini et al., 1984). Ultimately, however, this idea also failed because the putative organism could not be found in lesional tissues by sophisticated immunologic and culture techniques and because there was no evidence that the putative organism caused an immune response. The latter fact was particularly influential in light of the emerging belief among many students of the disease that IBD is basically an immunologic dysfunction.

The concept that IBD might be due to a nonallergic immunologic dysfunction was first seriously considered by Kirsner et al. (1961), who conducted the first series of studies of a possible immunologic dysfunction in IBD, taking the approach of creating animal models of bowel inflammation that resembled IBD. One such model was created in rabbits and was based on the "Auer" procedure, which consisted of stimulating antibody responses to a given antigen and then inducing mucosal deposition of antigen-antibody complexes by subsequently applying the antigen to the colon that had been preexposed to formalin (Kraft et al., 1963). An inflammation was thereby achieved that resembled ulcerative colitis histologically, but which differed from ulcerative colitis in that it was self-limited. In later studies by Mee et al. (1979), a similar rabbit model was created, except for the fact that investigators preimmunized the animals with E. coli, a member of the normal mucosal microflora (Mee et al., 1979), and the ulcerative colitis-like disease obtained was persistent. Taken together, these experiments suggested that IBD may result from an initial insult, followed by an inappropriate and sustained immunologic response to normal flora. A similar conclusion can be drawn from the almost forgotten studies of Halpern et al. (1967), who induced chronic ulcerative colitis-like lesions in rats by injecting the latter with strains of live or dead E. coli in Freund's adjuvant. Interestingly, in this case, the colitis could be prevented by prefeeding with E. coli, which in retrospect suggests that induction of tolerance with the inducing antigen (by feeding) affected colitis production and that colitis was a result of a failure of mucosal immunoregulation.

Later studies of animal models, conducted in the 1970s, enlarged on the previous themes. In one model studied during this period, the contactant dinitrochlorobenzene was used to induce colitis, providing an early suggestion that T cells rather than B cells might be the key elements in the inflammatory response of IBD (Onderdonk et al., 1978). In another model, it was shown that in mice and other animals wherein colitis had been induced by carrageenan, the coad-ministration of metronidazol prevented colitis induction (Broberger and Perelman, 1959).This again suggested a role of intestinal microflora. Overall, these early animal studies presaged current concepts of IBD that hold that both ulcerative colitis and Crohn's disease are due to an abnormality of immunoregulation and an inappropriate response to antigens in the mucosa environment.

The 1950s and 1960s, in addition to the above described animal model work, saw the advent of the first studies of human IBD from an immunologic point of view. The pioneering work that was conducted by Broberger and Perlmann (1959) and their various colleagues provided evidence that patients with IBD, particularly those with ulcera-tive colitis, developed antibodies to gut constituents, either bacterial antigens or cross-reactive self-antigens present in epithelial cells. Later it became apparent that these "autoan-tibodies" were most likely not disease specific and probably occurred secondary to tissue injury; nevertheless, they paved the way to future studies showing that ulcerative colitis is associated with the production of particular autoantibodies such as antineutrophil cytoplasmic antibody (ANCA) and antitropomyosin.

Perlmann and Broberger (1963) and their colleagues also introduced the idea that IBD was characterized by the development of cytotoxic cells, which were ultimately shown by Shorter et al. (1970) to be natural killer (NK) cells capable of mediating antibody-dependent cell-mediated cytotoxic reactions against epithelial cells, perhaps in conjunction with the antiepithelial cell antibodies alluded to earlier (Perlmann and Broberger, 1963; Shorter et al., 1970). This cytotoxicity phenomenon also proved to be disease nonspecific, but was nevertheless important because it focused attention on cellmediated immunologic processes as a cause of IBD. With these studies, the stage was now set for studies of T cells, first at the cellular level and later at the cytokine level (Hodgson et al., 1978; Elson et al., 1981). These, together with the newer animal models that have come along in the past 5 years, strongly suggest that ulcerative colitis and Crohn's disease represent different kinds of dysregulated mucosal immune responses induced by antigens in the normal microflora.

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