New Insights in the Pathogenesis of Autoimmune Hemolytic Anemia

Wilma Barcellini, Wilma Barcellini

Abstract

Autoimmune hemolytic anemia (AIHA) is caused by the increased destruction of red blood cells (RBCs) by anti-RBC autoantibodies with or without complement activation. RBC destruction may occur both by a direct lysis through the sequential activation of the final components of the complement cascade (membrane attack complex), or by antibody-dependent cell-mediated cytotoxicity (ADCC). The pathogenic role of autoantibodies depends on their class (the most frequent are IgG and IgM), subclass, thermal amplitude (warm and cold forms),as well as affinity and efficiency in activating complement. Several cytokines and cytotoxic mechanisms (CD8+ T and natural killer cells) are further involved in RBC destruction. Moreover, activated macrophages carrying Fc receptors may recognize and phagocyte erythrocytes opsonized by autoantibodies and complement. Direct complement-mediated lysis takes place mainly in the circulations and liver, whereas ADCC, cytotoxicity, and phagocytosis occur preferentially in the spleen and lymphoid organs. The degree of intravascular hemolysis is 10-fold greater than extravascular one. Finally, the efficacy of the erythroblastic compensatory response can greatly influence the clinical picture of AIHA. The interplay and relative burden of all these pathogenic mechanisms give reason for the great clinical heterogeneity of AIHAs, from fully compensated to rapidly evolving fatal cases.

Keywords: Autoantibodies; Autoimmune hemolytic anemia; Cytokines.

Figures

Fig. 1
Fig. 1
T-lymphocyte subsets and cytokine interactions in AIHA. Cytokines that were found elevated are highlighted in yellow: IL-2 and IL-12, that induce the differentiation of CD4+ naïve T cells into Th1 subset, and IL-4, that promotes Th2 switch. Elevated levels of TGF-β favor the differentiation of Th17 subset, which amplifies the pro-inflammatory and autoimmune response. On the contrary, decreased levels of both IFN-γ and Tregs were found (highlighted in green). The former resulted in decreased inhibition of Th2 response, i.e. an amplification of the autoantibody-mediated autoimmune disease, and the latter may cause a lack of down-regulation of inflammatory and autoimmune pathways.

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