Role of innate immunity's receptors and components of inflamassome in patients with ankylosing spondylitis

Abstract

Innate immunity is a nonspecific immune defense system found in all multicellular organisms. In mammals, it depends on fagocitic cells (neutrophils and macrophages), natural killers (NK) and dendritic cells. Besides, it is mediated by a group of receptors with limited repertoire, called pattern recognition receptors (PRR).Some microorganisms, pathogenic or not, share molecular structures known as pathogen associated molecular patterns (PAMP). These PAMP, for example, bacterial walls lipopolissacarides, are recognized by PRR of innate immune system cells. Toll-like receptors (TLR) are a family of PRR present in plasmatic membrane and endossome of antigen presenting cells (APC), which recognize microorganisms (bacteria, virus and fungi), stimulating synthesis and release of pro-inflammatory cytokines.Besides PAMP, TLR also connect to endogen molecules released actively or passively, during tissue necrosis, so called alarmines or DAMP (damage associated molecular pattern). NOD-like receptors are intracellular receptors of PAMP. The most studied is NALP-3, which once activated, works as complex able to recruit pro caspase-1 leading to constitution of a multimeric structure called inflamassome. This complex structure promotes production and release of IL-1beta and IL-8 cytokines. Both TLR and NLR act synergistically to produce IL-1beta. However, TLR increases the synthesis of pro-IL-1beta and NALPs activate caspase-1 to process it. Ankylosing spondylitis (AS) is an inflammatory disease characterized by sacroiliitis, enthesitis, osteitis and extra-articular signs as acute anterior uveitis and subclinic chronic colitis.There is a strong association between AS and HLA-B27, as well as other genes non-MHC, such as ERAP-1 and IL-23R. In addition, it has also been stated that some gut bacteria play a relevant role as a trigger and perpetuating antigenic immune process. Both aspects, genetic and environmental, have emphasized the involvement of innate immunity in the pathophysiology of AS.According to new evidences, AS can be triggered by acute, subacute and chronic infections. TLR is the main defense against microorganisms and it is also PAMP's receptor. Thus, some innate immune cells, such as CD163+ macrophages, express more often TLR and are involved in AS pathophysiology. De Rycke et al. observed significant expression of TLR-4 in peripheral blood monocytes of AS patients when compared with healthy controls. A Chinese study has also showed higher RNAm protein TLR-4 in AS subjects than in controls.The TLR's polymorphisms have been studied in AS with controversial results, especially due to population studied. There is some evidence of correlation between Asp299Gly and Thr399IIe polymorphisms and AS but other authors did not confirm that. The role of TLR in chronic inflammatory arthritis has been observed in some researches. Nevertheless, these studies were conducted in small samples and only considered Caucasian population. Mixed race patients, as Brazilian population, have never been evaluated. Besides, TLR is a potential therapeutic target and there is not any research that has investigated the association between the TLR's expression with the components of inflamassome, severity and disease activity in AS patients. (AU)