Developmental Phases of Inflammation-Induced Massive Lymphoid Hyperplasia and Extensive Changes in Epithelium in an Experimental Model of Allergy

Abstract

Direct evidence that inflammation is linked to carcinogenesis has yet to be established. Very few data are available on the developmental phases of inflammation-induced immune dysfunction that may lead to tumorigenesis. In a series of studies conducted in the 1980s and 1990s, an experimental model of acute and chronic inflammation was established in guinea pig conjunctiva by topical application of fluoresceinyl ovalbumin (FLOA) for up to 30 months. In this updated report, some of the findings are reanalyzed and expanded to identify that at lease 3 developmental phases were involved during the entire course of inflammatory responses including (1) an acute response (phase A) involving IgE-mast cell sensitization and degranulation; (2) an intermediate phase (phase B), a desensitization phenomenon and loss of mast cell function and neovascularization; (3) a chronic response (phase C) and induction of massive lymphoid hyperplasia, follicular formation with germinal centers, increased swollen goblet cells, extensive epithelial thickening and thinning, and angiogenesis. The results suggest evidence of a direct association between inflammation and the development of tumor-like lesions in lymphoid tissues and extensive changes in adjacent epithelia. Confirmation that inflammation induces irreversible changes in lymphoid and epithelial tissues leading to lymphoid tumorigenesis and/or carcinogenesis requires further studies. Understanding the developmental phases of immune dysfunction may provide unique opportunities for diagnosis and treatment of inflammatory diseases, autoimmune disorders, and cancers including lymphomas associated with Sjogren syndrome, squamous cell carcinoma of the conjunctiva, and other lymphomas or epithelial cancers. It is suggested that inflammatory mediators are ideal targets (biomarkers) for diagnosis, chemoprevention, and therapy for several cancers.

Inflammation, Aging, and Cancer: Tumoricidal Versus Tumorigenesis of Immunity

“…Th1 mediators (e.g., IFN-c, IL-2, TNF-a, and lymphotoxin) are expressed often in response to intracellular pathogens, while Th2 mediators (e.g., IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13) are generated in response to extracellular pathogens or infective agents [1,2,28,34,54,68,69,[103][104][105][106][107][108][109]. Impaired expression and/or function of Th1 mediators have been associated with exaggerated HI and generation of strong-abnormal antibody biosynthesis or isotype switching responses (e.g., IgG to IgE or changes in IgG1/IgG2 biosynthesis) in certain inflammatory disorders such as giant papillary conjunctivitis, conjunctival squamous cell carcinoma, accelerated progression in HIV-AIDS, autoimmune diseases, sarcoidosis, Crohn's disease, atopic and delayed hypersensitivity reactions, allograft tolerance, and/or hyperplasia of lymphoid tissues, tumor growth, and angiogenesis [1,2,11,23,38,40,58,59,65,70,88,[107][108][109][110][111][112][113][114][115][116][117][118][119].…”

“…The immune system can recognize external foreign (nonself, stimuli) elements such as bacteria, viruses, parasites, fungi, chemical or environmental hazards, and carcinogens, as well as internal stimuli such as exaggerated production of lymphocytes clonal expansion, polyclonal complexes that are produced during tissue stimulation, senescence or mature and terminally differentiated cells (e.g., effector T cells) that no longer function (self-antigens), and/or excess oxidants and metabolites (e.g., uric acid crystal formation, oxidized lipids, cholesterol, homocysteine, oxidized GSH, or vitamins), mutated DNA/RNA, incorrectly synthesized proteins/peptides, or cancerous cells [1][2][3][28][29][30][31][32][33][34][35][36][37][38][39][40].…”

“…Central tolerance pathways often fail to eliminate all self-reactive or terminally differentiated cells (e.g., effector cells or clonal expansion), or peripheral tolerance. Therefore, other immune mechanisms are required to inhibit or control the exaggerated and inappropriate immune responses [1,2,[28][29][30][31][32][33][34][35][36][37][38][39][40].…”

Erlotinib protects against LPS-induced Endotoxicity because TLR4 needs EGFR to signal

“…TRIF-dependent signaling involves a slower activation of NFκB and also activation of IFN regulatory factor 3 (IRF3), leading to the production of type I IFN (IFN α/β), IFN-inducible gene products, and the full innate immune response (25). It is well-known that chronic inflammation can facilitate the development of cancer (26)(27)(28)(29) and TLR4 plays a key role in carcinogenesis. It has been reported that…”

Role of the Neutrophil NADPH Oxidase and S100A8/A9 in the Pathophysiology of Chronic Inflammation

“…Chronic inflammation was hypothesized as the loss of balance between apoptosis and wound healing leading to disruption of protective mechanisms of immune system (Khatami, 2005(Khatami, , 2008(Khatami, , 2009. Unresolved inflammation-induced excessive expression of proand anti-inflammatory mediators causes erosion of tissue integrity initiating the development of chronic inflammatory diseases or cancer (Khatami, 2011).…”