Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of >30 lymphoid neoplasms, >85% of which are of B cell lineage. NHL presents a considerable public health burden with >80,500 new diagnoses and 24,600 deaths expected in 2010. The etiology of NHL is poorly understood, but it is known that overt immune compromise is a strong risk factor. Immune dysregulation may also be important in the etiology of NHL in persons with no overt immune deficiency. The Epstein-Barr virus (EBV) is detected in a sizeable minority of NHL in immune competent persons, but neither the true prevalence nor risk factors for EBV+ NHL are known. Th17, Th1, and Th2 cytokines mediate human immune responses and may be associated with NHL risk by virtue of their roles in B and T lymphocyte activation and inflammation. The Th17 response leads to the induction of several B cell stimulatory cytokines;this axis is also implicated in autoimmune disease, and persons with autoimmune conditions have an increased risk of NHL. It is plausible that Th17 dysregulation, and/or dysregulation of Th1 or Th2 or inflammatory responses, is associated with NHL risk in apparently immune competent adults. Cytokines also mediate host control of EBV and thus may also predict risk of EBV+ NHL. To examine these hypotheses, we will conduct prospective studies nested within the Nurses'Health Study and Health Professionals Follow-up Study cohorts. In a projected pooled sample of 670 cases and 1340 matched controls, we will measure a panel of immune markers in pre-diagnostic plasma samples. We will collect tissue specimens from NHL cases for pathologic studies to determine WHO-defined histologic subtype, diffuse large B-cell lymphoma (DLBCL) molecular subtype, and EBV status. We will use conditional logistic regression to assess the association of plasma immune markers indicative of altered Th17, Th1, Th2 and/or inflammatory responses with NHL. We will evaluate confounding by other NHL risk factors and conduct secondary analyses to examine effect modification and explore the correlation of plasma immune markers with those other factors. With these studies we will be the first to examine the etiologic role of the Th17 response in NHL, to report population-based prevalences of EBV+ NHL by subtype and of DLBCL subtypes, and to prospectively evaluate risk factors for EBV+ NHL. The multidisciplinary study team features epidemiologists (Drs. Birmann, Laden, and Giovannucci), a senior biostatistician (Dr. Rosner), and immunologists (Drs. Martmnez-Maza and Breen) and hematopathologists (Drs. Aster and Rodig) with substantial relevant experience-i.e, in the use of plasma immune markers in etiologic studies, prospective data analysis, and the pathologic determination of NHL histologic type and tumor EBV status. With this highly qualified team, the extraordinary resources of the cohorts, and the proposed studies, we are uniquely situated to contribute novel insights on the role of immune dysregulation in the etiology of NHL and EBV+ NHL in immunocompetent adults. PUBLIC HEALTH RELEVANCE: Non-Hodgkin lymphoma (NHL) is the 6th most common cancer diagnosis in the US and is sometimes associated with Epstein-Barr virus (EBV) infection. The studies proposed in this application involve testing blood samples for levels of cytokines, which are hormones that drive immune responses, to evaluate whether risk of different types of NHL or EBV-associated NHL is related to cytokine imbalances in apparently healthy persons. The findings may be useful for identifying people at a higher risk for these cancers, the causes of which remain poorly understood.