**2.2.1 Immunodeficiency and autoimmune disease**

Immunodeficiency, including acquired conditions and congenital disease, is the strongest factor known to increase NHL risk (Chiu & Weisenburger, 2003). About 25% of patients with congenital immunodeficiency syndromes such as Wiskott-Aldrich syndrome, ataxia telangiectasia and severe combined immunodeficiency, will develop tumors during their lifetime, which NHL accounting for 50% of them. It seems that these patients unable to promptly eliminate respiratory and gastrointestinal pathogens due to defects in formation of specific protective antibodies and are susceptible to chronic antigenic stimulation (Filipovich, Mathur, Kamat, & Shapiro, 1992).

High rate of NHL also have been observed among individual with iatrogenic immunosuppression (i.e. organ or blood stem cell transplantation recipients, long term survivors of Hodgkin's lymphoma), variety of autoimmune disease, and Acquired immunodeficiency syndrome (AIDS). Although immunosuppressive drug use in the treatment of these conditions may cause an increase in NHL incidence, evidence suggests that the persistent inflammatory activity of the autoimmune process may have a direct relation with increase risk of lymphomagenesis. One study showed that these conditions may be accompanied by impaired T-cell function, which interferes with an immune response to virus and emerging malignant cells. NHL due to secondary immunodeficiency is associated with the presence of EBV infection, and tumors are characterized by high grad, and proclivity for extra-nodal sites (Fisher & Fisher, 2004). Based on these data immunodeficiency may be more common in some area which aggressive lymphoma is more common such as Asian countries.

Autoimmune disorders that are strongly associated with NHL are Sjogren's syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, and celiac disease (CD). There is no evidence to support excess risk of NHL in other autoimmune disorders. One study demonstrated a 25-fold increase in the risk of NHL among persons with highly inflammatory RA as compared to a similar group having low inflammatory disease; this risk was independent of treatment (Fisher & Fisher, 2004). Finding in the other study suggests that the excess risk of NHL in RA patients may be a result of the disease or its treatment, rather than shared genetic susceptibility (Ekström, et al., 2003; Kinlen, 1992).

Celiac disease is an autoimmune digestive disease which is caused by an immune response to the protein gluten. Untreated CD is associated with increased risk of lymphoma, mostly with origins from gastrointestinal mucosa. The pathogenesis behind this association is not fully understood, but greater permeability to environmental carcinogenesis, release of proinflammatory cytokines , and chronic antigenic stimulation are among the suggested

and decreasing childhood gastroenteritides in particular has resulted in a decrease in the incidence of IPSID. This report highlights the almost complete disappearance of a malignant disease from a region where it was once very common. This changes probably related to changes in environmental factors, decreasing exposure to infectious agents (Lankarani, et al., 2005). Other preliminary recent epidemiological data has also shown a decrease in the incidence of this disease in endemic areas; therefore, environmental factors are suspected to

Immunodeficiency, including acquired conditions and congenital disease, is the strongest factor known to increase NHL risk (Chiu & Weisenburger, 2003). About 25% of patients with congenital immunodeficiency syndromes such as Wiskott-Aldrich syndrome, ataxia telangiectasia and severe combined immunodeficiency, will develop tumors during their lifetime, which NHL accounting for 50% of them. It seems that these patients unable to promptly eliminate respiratory and gastrointestinal pathogens due to defects in formation of specific protective antibodies and are susceptible to chronic antigenic stimulation

High rate of NHL also have been observed among individual with iatrogenic immunosuppression (i.e. organ or blood stem cell transplantation recipients, long term survivors of Hodgkin's lymphoma), variety of autoimmune disease, and Acquired immunodeficiency syndrome (AIDS). Although immunosuppressive drug use in the treatment of these conditions may cause an increase in NHL incidence, evidence suggests that the persistent inflammatory activity of the autoimmune process may have a direct relation with increase risk of lymphomagenesis. One study showed that these conditions may be accompanied by impaired T-cell function, which interferes with an immune response to virus and emerging malignant cells. NHL due to secondary immunodeficiency is associated with the presence of EBV infection, and tumors are characterized by high grad, and proclivity for extra-nodal sites (Fisher & Fisher, 2004). Based on these data immunodeficiency may be more common in some area which aggressive lymphoma is more

Autoimmune disorders that are strongly associated with NHL are Sjogren's syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, and celiac disease (CD). There is no evidence to support excess risk of NHL in other autoimmune disorders. One study demonstrated a 25-fold increase in the risk of NHL among persons with highly inflammatory RA as compared to a similar group having low inflammatory disease; this risk was independent of treatment (Fisher & Fisher, 2004). Finding in the other study suggests that the excess risk of NHL in RA patients may be a result of the disease or its treatment,

Celiac disease is an autoimmune digestive disease which is caused by an immune response to the protein gluten. Untreated CD is associated with increased risk of lymphoma, mostly with origins from gastrointestinal mucosa. The pathogenesis behind this association is not fully understood, but greater permeability to environmental carcinogenesis, release of proinflammatory cytokines , and chronic antigenic stimulation are among the suggested

rather than shared genetic susceptibility (Ekström, et al., 2003; Kinlen, 1992).

play an important role in its pathogenesis (P. A. Salem & Estephan, 2005).

**2.2.1 Immunodeficiency and autoimmune disease** 

(Filipovich, Mathur, Kamat, & Shapiro, 1992).

common such as Asian countries.

**2.2 Epidemiologic etiology** 

mechanisms. Also a correlation between the duration of gluten exposure and the incidence of lymphoma has been found. The relative risk of lymphoma is reduced by a gluten free diet (Jafroodi, Zargari, & Hoda, 2009). In a US cohort study, an increased risk of NHL was reported in patients with celiac disease (SMR = 9.1, 95% CI: 4.7-13.0). Similarly, a relative risk of 5.8 (95% CI: 1.58-14.86) was observed in a UK cohort (Alexander, et al., 2007).

The incidence of CD is increasing among certain populations in Africa (Saharawui population), Asia (India), and the Middle East (Cummins & Roberts Thomson, 2009). In Asian populations, including the Japanese, CD and the associated NHL have been supposed to be quite rare, and studies concerning the frequency of CD or its relationship with NHL are scarce. A Japanese case report describes a Japanese middle-aged man with intestinal diffuse large B-cell lymphoma associated with CD. Following multi-combined chemotherapy, the patient's lymphoma has received complete response, and his GI symptoms have improved with a gluten free diet (Makishima, et al., 2006). Also an Iranian case report describes a child with Hodgkin's disease and sever atopic dermatitis associated with CD (Arellano, et al., 2009). These cases suggest that the possibility of CD and its association with lymphoid malignancy should be kept in mind, even in Asian populations.
