Uniba.sk



Autoinflammatory diseasesMilan BucA characteristic feature of autoinflammatory diseases is, as the name suggests, that the affected will develop inflammatory processes without an apparent infectious cause. The original name of these diseases was periodic fever, whose name reflected clinical observations of recurrent fever. Each autoinflammatory syndrome is a mixture of symptoms including fever, abdominal pain, arthralgia, arthritis, and lymphadenopathy and skin manifestations. A fever attack always accompanies a significant increase in the levels of acute phase proteins (CRP, SAA) and leucocytosis. Autoinflammatory diseases typically develop as a result of mutation in one of the immunoregulatory genes, causing excessive cytokine production and the development of inflammation. This is primarily a mutation of genes that are involved in the regulation of natural immunity.What is the relationship between autoinflammatory (AID) and autoimmune diseases (AUD)? Both are the result of chronic activation of the immune system, which ultimately causes tissue inflammation in genetically predisposed individuals. Nevertheless, there is a fundamental difference in effector mechanisms: in AICH, tissue inflammation is directly caused by the mechanisms of innate immunity, whereas in AUD, natural immunity first activates adaptive immune mechanisms and only then induces an inflammatory process. In patients suffering from some AID, compared to those with AUD, we never find either autoantibodies or autoreactive T cells, which is so characteristic of autoimmune diseases. The difference between AID and AUD also relates to the HLA complex. Autoimmune diseases are known for their association with HLA alleles or HLA haplotypes, whereas no such association is observed in autoinflammatory diseases. As far as genetic determination is concerned, AID is predominantly monogenic over polygenic, whereas AUD is the opposite.In the following sections we describe as an example four diseases, whose pathogenesis is already well known, which subsequently enabled the development of adequate treatment.Familiar Mediterranean Fever Familiar Mediterranean Fever (FMF) was discovered in 1997. Its name is derived from the fact that it is found mainly in individuals living in the Mediterranean region, i.e. Turks, Jews, Armenians and Arabs; it also sporadically affects other nations. It is caused by a mutation of the MEFV gene, located on the short arm of the 16th chromosome (16p12). MEFV encodes a protein called pyrine. It is mainly expressed in neutrophils and monocytes. Pyrine, with its PYD domain, binds to the same domain of other proteins, e.g. to ASC (apoptosis-associated speck-like protein containing CARD; CARD caspase activation and recruitment domain). Subsequently, procaspase 1 is binds to the ASC by its CARD domain; by this binding it is activated and converted to active caspase 1. The pyrine, ASC and procaspase 1 complex is referred to as an inflamasome. Caspase 1 cleaves inactive proIL-1β into active IL-1β, a known pro-inflammatory cytokine. Mutations cause pyrine to promote dimerization of ASC-molecules with consequent increased IL-1β production. ASC is also an important molecule for the function of the NLRP3. The PYD-domain of the ASC protein interacts with the PYD-domain of NLRP3, allowing procaspase 1 to bind to its CARD-domain. Binding activates and active caspase 1 subsequently allows pro-inflammatory cytokines IL-1β and IL-18 to develop. Pyrine competes with the ACS-protein for binding to NLRP3, being its physiological negative regulator. Certain mutations in the MEFV gene cause pyrine to lose its negative function, resulting in uncontrolled NLPR3 activity and excessive synthesis of pro-inflammatory cytokines.The disease characterize repeated attacks of fever and serositis (peritonitis, pleuritis, pericarditis, rarely meningitis). Elevated levels of SAA cause renal failure due to amyloidosis. Colchicine is the treatment of first choice for FMF. Although it has been used since the 1970s, the mechanism of action of colchicine is still unknown. It is highly effective in preventing attacks. Response to colchicine has been used as a diagnostic criterion for FMF.Auto-inflammatory diseases associated with cryopyrinAuto-inflammatory diseases associated with cryopyrin or according to the old nomenclature "Cryopyrin-associated periodic syndrome" or cryopathies, include three diseases: Muckle-Wells syndrome (MWS), familial cold urticaria (FCU) and systemic inflammatory disease beginning with neonatal age (NOMID Neonatal-onset multisystem inflammatory disease; another name of this disease is Chronic infantile neurological, cutaneous and articular syndrome CINCA). These autosomal-dominant, seemingly different diseases are linked by a common nature mutations in the NLRP3 gene (1q44), previously called cryopyrin, from which the name for these diseases was derived.NLRP3 recognizes signals not only from the external (PAMP), but also the internal environment of the organism, which are the result of damage to its cells (alarmins). In addition, it also recognizes molecules of exogenous origin that can also induce inflammation, such as e.g. asbestos or silica, inducing asbestosis, resp. silicosis and pulmonary interstitial fibrosis. Both endogenous and exogenous DAMPs induce the mobilization of neutrophils and macrophages and the induction of proinflammatory cytokine production, in particular IL-1 and TNF; as germs do not induce this inflammation, it is termed sterile. CAPS result from mutations in the third exon of the NLRP3 gene, which encodes an oligodimerization domain. As a result, they easily NLPP3 molecules homodimerize even on little pro-inflammatory stimuli, e.g. via Toll-like receptors, or even spontaneously, which causes inflammatory activation and IL-1 production. Systemic inflammation manifests itself by fever, tiredness, loss of energy, and myalgias. In children is there a growth retardation. Systemic inflammation results in amyloidosis development. It is a group of diseases, in which abnormal proteins, called amyloid fibres, deposit into tissues. The presentation of amyloidosis is broad and depends on the site of amyloid accumulation. The kidney and heart are the most common organs involved. As already mentioned, there are three diseases included into cryopaties and they are characterized by their own specific symptoms.Deficiency of the Interleukin-1–Receptor Antagonist DIRA syndromeIL-1 is the strongest known pro-inflammatory cytokine. It exists in two basic forms, IL-1 and IL-1. IL-1 molecules are typically synthesized in the form of high molecular weight propeptides without a signal peptide. Pro-IL-1 is biologically as active as its final cleavage product and, upon synthesis, moves to the nucleus of the cell from which is released by necrosis; therefore represents alarmin. A small portion of pro-IL-1β is also found in the cell membrane and is biologically active, acting in paracrine manner. Pro-IL-1 is inactive and only enters active form after intracellular caspase 1 cleavage. IL-1 performs its function by binding to its receptor, which consists of a chain specifically binding IL-1 (IL-1R), a signal transduction chain (IL-1RAcP IL-1 receptor accessory protein) and an adapter protein MyD88, which attaches to the complex only after ligand binding. The signaling pathways result in the activation of numerous genes whose products are further involved in the development of the immune response.IL-1 has its natural inhibitor IL-1Ra (IL-1 receptor antagonist). It is structurally similar to both IL-1 and IL-1, but is biologically inactive and does not transmit any signal upon binding to IL-1 receptors. Its non-functional form due to gene mutation (IL-1RN, chromosome 2; autosomal-recessive inheritance) or complete lack results in DIRA-syndrome (deficiency of the IL-1 receptor antagonist). The disease manifests itself early in the neonatal period and manifests by inflammation of the bone (ostitis), bone marrow (osteomyelitis) and skin (pustule formation).Biological therapy of CAPS and DIRA is based on inhibition of IL-1β activities. The first inhibitor of IL-1 developed was the recombinant human IL-1 receptor antagonist anakinra. It competitively binds to the IL-1 receptor, completely inhibiting the actions of both IL-1α and IL-1β. Anakinra has a short half-life and needs to be given once a day subcutaneously. Rilonacept is a construct of two extracellular chains of the IL-1 receptor complex fused to the Fc-portion of IgG. It is given once weekly, subcutaneously. The selective anti-IL-1β monoclonal antibody canakinumab has a longer half-life and is injected subcutaneously too. Standard injection frequency is once per 8 weeks.Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)Mutations in the gene TNFRSF1A are responsible for TRAPS. This gene encodes the TNF-receptor 1 (p55), the main cell surface receptor for TNF (the second receptor is p75). This receptor consists of three domains: an extracellular ligand-binding domain, a transmembrane domain, and an intracellular effector domain. Upon ligand binding by the extracellular receptor domain, the TNFR forms trimers, triggering the recruitment of intracellular adaptor proteins, which initiate a downstream signalling cascade, leading to production of proinflammatory cytokines and caspase-induced apoptosis. When the receptor is activated, the extracellular domain of the TNFR is shed from the membrane. These shed receptors form an extracellular pool of soluble TNFRs, retain their affinity for binding TNF, and are therefore able to downregulate the immune response. Initially, it was suggested that TRAPS-associated mutations would lead to defective shedding of TNFR1 receptors, but this hypothesis was discarded as the major pathogenetic mechanism for TRAPS after in vitro experiments showed misfolding and intracellular accumulation of mutated proteins. These aggregated receptors retain their normal signalling function and can induce ligand-independent signalling resulting in inflammation. TRAPS is inherited in an autosomal dominant fashion. Age of onset varies widely. Many patients become symptomatic within the first years of life, but adult onset is also possible. The usual duration of fever in TRAPS is considerably longer than in the other classic autoinflammatory syndromes: attacks persist for a minimum of 3 days but can last for several weeks. The interval between attacks in a single patient can vary substantially.Localized myalgia, a deep cramping, and often severely disabling pain in a single limb resulting from monocytic fasciitis and associated with fever is found in virtually all patients. The affected limb may show local erythema, which may migrate to the distal part of the extremity. Almost all patients have abdominal pain, often accompanied by vomiting, constipation, and bowel obstruction. Arthralgia and monoarthritis may be present. Chest pain is frequent and can be caused by pleuritis. Ocular symptoms range from conjunctivitis and periorbital pain to severe uveitis and iritis. Because TNF and IL-1 are the principal proinflammatory cytokines involved in pathogenesis of TRAPS, their inhibitors should be used for the treatment. Three widely used inhibitors of TNF are the monoclonal antibodies infliximab and adalimumab and the recombinant soluble TNF receptor etanercept. The latter shows better response. However, generally, TNF inhibition induces complete response only in a minority of patients with TRAPS. Therefore, anti–IL-1 treatment should be preferred.There are more autoinflammatory diseases than those described above. The list of them is given in the table and more details can be found in numerous articles and textbooks. ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download