Abstract
Autoinflammation is defined by aberrant, antigen-independent activation of the innate immune signaling pathways. This leads to increased, pro-inflammatory cytokine expression and subsequent inflammation. In contrast, autoimmune and allergic diseases are antigen-directed immune responses from activation of the adaptive immune system. The innate and adaptive immune signaling pathways are closely interconnected. The group of ‘complex multigenic diseases’ are a result of mutual dysregulation of both the autoinflammatory and autoimmune physiologic components. In contrast, monogenic autoinflammatory syndromes (MAIS) result from single mutations and are exclusively autoinflammatory in their pathogenesis. Studying the clinical and histopathological findings for the various MAIS explains the phenotypical correlates of their specific mutations. This review aims to group the histopathologic clues for autoinflammation into three recognizable patterns. The presence of these histologic patterns in a pediatric patient with recurrent fevers and systemic inflammation should raise suspicion of an autoinflammatory component in MAIS, or, more frequently, in a complex multigenic disease. The three major histopathological patterns seen in autoinflammation are as follows: (i) the ‘neutrophilic’ pattern, seen in urticarial neutrophilic dermatosis, pustular psoriasis, aseptic neutrophilic folliculitis, and Sweet’s syndrome; (ii) the ‘vasculitic’ pattern seen in small vessel-vasculitis (including hypersensitivity/leukocytoclastic vasculitis, thrombosing microangiopathy and lymphocytic vasculitis), and intermediate-sized vessel vasculitis, mimicking polyarteritis nodosa; and (iii) the ‘granulomatous’ pattern. Beyond these three patterns, there are additional histopathologic clues, which are detailed below. It is important for a dermatopathologist to recognize the patterns of autoinflammation, so that a diagnosis of MAIS or complex multigenic diseases may be obtained. Finally, careful histopathologic analyses could contribute to a better understanding of the various clinical manifestations of autoinflammation.
Highlights
IL-36RN is a negative regulator of IL-36 receptor signaling, and loss of function is present in the monogenic syndrome called deficiency of IL-36 receptor antagonist syndrome (DITRA) and in complex multigenic diseases such as generalized pustular psoriasis, palmoplantar pustular psoriasis, and acrodermatitis continua of Hallopeau
The monogenic autoinflammatory syndromes (MAIS) that produce small-sized vessel vasculitis include leukocytoclastic vasculitis, the thrombotic microangiopathy seen in the interferonopathies, and the lymphocytic vasculitis seen in tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
Thrombotic microangiopathy is the histopathological hallmark of the interferonopathies, all characterized by mutations that lead to the aberrant release of type I IFN and inflammation simulating viral infection or systemic lupus erythematosus (LE)
Summary
Autoinflammatory Versus Autoimmune Disease—What the Dermatopathologist Needs to Know. Dysfunction of innate immunity is rare and results from an antigen-independent hyperactivation of molecular pro-inflammatory pathways, leading to ‘autoinflammatory’. Dysfunction of adaptive immunity is frequent and results from non-pathogen activation of inflammation. The inherited diseases that cause autoinflammation, called ‘monogenic autoinflammatory syndromes’ (MAIS), are characterized by recurrent fever, increased cytokine expression, and episodic inflammation, resulting in potential end-organ damage. In contrast to autoimmune diseases, the increased, chronically active cytokine expression does not require auto-reactive lymphocytes or immunoglobulins to self-antigens. MAIS may be triggered by an infectious pathogen, their hallmark is the persistence of inflammation in the absence of a recognizable infection [2,3,4,5,6] Despite these differences, autoinflammation and autoimmunity are interlinked. This dysregulation of innate immunity is interdependent with adaptive immunity
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