Gastropathies of autoimmune origin Enzo Ierardi Sezione di Gastroenterologia Dipartimento delle Scienze Mediche e del Lavoro Università degli Studi di Foggia

Gastropathies of autoimmune origin historical antecedents outstanding discoveries unresolved problems Whittingham & MacKay, Int Rev Immunol. 2005

historical antecedents The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, when Thomas Addison described "a very remarkable form of anemia" later called pernicious anemia This was followed by the recognition of a gastric mucosal defect suspected to have a nutritional basis

historical antecedents discovery of: the megaloblast that characterized the anemia insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin) treatment with vitamin B12 proved curative gastric-secreted intrinsic factor

outstanding discoveries The link between pernicious anemia and gastritis/atrophy was first confirmed: histologically after immediate fixation of the stomach postmortem later, in the 1940s, by peroral tube biopsy The causes of gastritis remained enigmatic until the era of autoimmunity, when: autoantibodies were detected first to gastric intrinsic factor then to gastric parietal cells

outstanding discoveries Hints of a dichotomy in pathogenesis of gastritis were clarified by the description in 1973 of Type A (Autoimmune) and Type B gastritis of unknown origin Clarification was enhanced by identification in Type A gastritis of the autoantigen of the parietal cell antibody, by the alpha and beta subunits of gastric H+/K+ ATPase

outstanding discoveries Type B gastritis causative role of gastric infection with Helicobacter pylori Warren & Matshall, 1983 Experimental autoimmune gastritis: mouse models of human organ-specific autoimmune disease Field et al, 2005

Animal model Lymphnodes Th1 The disease is induced in the regional gastric lymph node (pathogenic CD4+ T cells are recruited) Regulation by CD4+CD25+T cells, and removal of such regulatory cells by neonatal thymectomy is the major mechanism by which disease can develop The culprit T helper type 1 (Th1) CD4+ T cells recognize either the alpha- or beta-subunits of the gastric H+/K+ ATPase The beta-subunit appears to be the initiating autoantigen, while the alpha-subunit may have a role in perpetuating disease Lymphnodes Th1

Animal model thymus The two subunits of the gastric H/K ATPase, i. e. the catalytic alpha-subunit and the glycoprotein beta-subunit, are the major targets of parietal cell autoantibodies associated with human and murine autoimmune gastritis The beta-subunit appears to be the initiating autoantigen, while the alpha-subunit may have a role in perpetuating disease Expression of the gene of gastric H/K-ATPase alpha-subunit in the thymus may explain the dominant role of the beta-subunit in the pathogenesis of autoimmune gastritis Alderuccio et al, Autoimmunity, 1997 Th1

­ ¯ patterns of Type B gastritis HCl Site - duodenal gastric absent Antrum – 80% Antrum + Body 20% Gastric pathology HCl output Duodenal peptic disease - Chronic active gastritis - atrophy - intestinal metaplasia ¯ ­ duodenal gastric - duodenitis - gastric Dixon ,1994

¯ pattern of Type A gastritis HCl Site risk carcinoma absent output gastric pathlogy HCl output duodenal diseases risk - atrophy intestinal metaplasia ¯ carcinoma Body

GASTRITIS – CARCINOMA SEQUENCE intestinal metaplasia and atrophy carcinoma Correa, 1993 Both Type A (100%) and Type B (20%) gastritis are precancerous conditions

antibodies to parietal cells unresolved problems Type B gastritis and immunity Helicobacter pylori  “antigenic mimicry” antibodies to parietal cells  atrophy Negrini, Gastroenterology 1992-1996

unresolved problems IMMUNOHISTOCHEMICAL REACTION OF HP+ SERUM WITH AUTOLOGOUS PARIETAL CELLS

unresolved problems Increased values of incidence and prevalence of Helicobacter pylori infection in geographic areas with high diffusion of gastric carcinoma Forman, 1990 (Cina) Chen, 1990 (Colombia) Increased risk of gastric carcinoma in patients who aquire Helicobacter pylori in pediatric age Sipponen, 1993

unresolved problems Autoantibodies reacting with gastric antigens in Helicobacter pylori associated body gasritis in dyspeptic children Ierardi, 1998 ? The H. pylori related autoreaction to gastric mucosa could be followed by the appearance of circulating autoantibodies to parietal cells thus suggesting a sequential link between types B and A gastritis The H. pylori related autoreaction in the stomach and the presence of serum autoantibodies to parietal cells are indipendent phenomena expressed in different types of gastritis

unresolved problems HP related gastric atrophy as result of cross reaction to parietal cells target of reaction represented by canalicular H+/K+ ATPase protonic pump Appelmelk, 1996-1997 Faller, 1996-1998

H. PYLORI AND AUTOIMMUNITY unresolved problems H. PYLORI AND AUTOIMMUNITY It is possible that the long-term damage of infected mucosa may expose to immune system even "self" components Bacterial “soma” exposes to immune system blood Lewis x ed y antigens, which are absolutely similar to that of protonic pump ATPase and mucin Once atrophy has developed, bacteria show the tendency to disappear and antibody titres reach the level of seronegativity In this phase phenomena of autoimmunity or malignacy may appear and be sustained independently by the initial antigenic stimulus Torelli, 2006

LOW GRADE MALT GASTRIC LYMPHOMA unresolved problems LOW GRADE MALT GASTRIC LYMPHOMA B lymphocytes (atypic clones) with tendency to diffuse in the lamina propria and epithelium

MALT LYMPHOMA MEETS H. PYLORI Hp in more than 90% of primary gastric lymphomas Hp associated to the development of lymphoid aggregates with germinal centres (MALT tissue) MALT is not found in a normal stomach !!!!! Wotherspoon et al, Lancet 1991

EVIDENCES FOR A ROLE OF H. PYLORI IN MALT LYMPHOMA Epidemiologic Experimental Clinic

Experimental evidences Th1 B Crabtree et al, Lancet 1993 Tumoral immunoglobulins

“tumoral immunoglobulins” Immunoglobulins with heavy chains (IgH) May be identified in paraffin embdedded tissues by a PCR method described by Wan et al in 1992 (J Clin Pathol) Five successive studies confirmed its sensitivity and suitability (Algara 1993, Ling 1993, Diss 1994, De Re 1995 e Lozano 1996)

Pattern of tumoral immunoglobulins unresolved problems Pattern of tumoral immunoglobulins B Th1 AUTOIMMUNITY (?) Spencer et al, J Pathol 1990 Griner et al, Lab Invest 1994

Chronic erosions of the stomach unresolved problems Chronic erosions of the stomach Erosions which arise on mucosal nodular elevations, oftel located in the antrum, not suitable of bleeding and often characterized by absenct or dyspeptic symptoms Elta, 1986 Invoked causes: H. pylori, chemical injury due to bile reflux or NSAIDs (Type C gastritis), chronic ischaemia

FOOD SENSITIZATION AND RECURRENCE FREQUENCY IN PATIENTS WITH CHRONIC GASTRIC EROSIONS among significant factors in pathogenesis of chronic gastric erosions, the infectious-allergic factor is essential high titers of specific IgE antibodies to infectious, home, food and plant allergens are found persistence in remission of high and moderate titers of specific IgE indicated chronicity of the disease and expected recurrence Sboichakov et al, 2002 Humoral and cellular responses to cow milk proteins in patients with milk-induced IgE-mediated and non-IgE-mediated disorders Shelk et al, Allergy 2005

Gastropathies of autoimmune origin and uncertain clinical significance unresolved problems Gastropathies of autoimmune origin and uncertain clinical significance Lymphocytic gastritis (celiac disease) Eosiniphilic gastroenteritis Others