Buc M Antigen recognition by adaptive immunity B and T cells express specific receptors that are able to recognize 10 9 till 10 ID: 1047611
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1. Autoinflammatory diseasesBuc M
2. Antigen recognition by adaptive immunityB and T cells express specific receptors that are able to recognize 109 till 1012 various antigensNat Rev Immunol
3. Antigen recognition innate immunityInnate immunity compared to adaptive immunity recognizes a tiny fraction of antigens.However, microbial antigens recognized by innate immunity belong to highly conservative molecules and are indispensable for their life. Moreover, cells of our body do not express them.The term „pathogen associated molecular patterns“ (PAMPs) was coined for them and receptors that recognize PAPMs are known under the term “pattern recognition receptors“ (PRRs).
4. 4Trinity of the most important PRRsTLRs – recognize all type of germsNLRs – recognize bacteriaRLRs – recognize virusesTrends Immunol
5. Abbas K et al. Immunology 2018
6. Pathogens are not the only causative agents of tissue and cell damage, tissues can be damaged also by trauma, burns, cold, chemical insults, radiation, the withdrawal of oxygen and/or nutrients, etc. Humans can also be damaged by drugs, such as chemotherapeutics, which kill tumour cells, however they may damage also healthy cells.The term “alarmins” was coined for these endogenous molecules that signal tissue and cell damage. Alarmins and PAMPs therefore constitute the family of damage-associated molecular patterns DAMPs (DAMPs = PAMPs + alarmins)Alarmins and DAMPs
7. Nucleic acidsssRNAVirusesdsRNAVirusesCpGViruses, bacteriaProteinsPilinBacteriaFlagellinBacteriaCell wall lipidsLPSGram-negative bacteriaLipoteichoic acidGram-positive bacteriaCarbohydratesMannanFungi, bacteriaGlucansFungiPathogen-Associated Molecular Patterns
8. AlarminsStress-induced proteinsHSPsCrystalsMonosodium urateProteolytically cleaved extracellular matrixProteoglycan peptidesMitochondria and mitochon. componentsFormylated peptides and ATPNuclear proteinsHMGB1, histonesCytokinesIl-1
9. Uric acid as an alarminUric acid is present not only in the cytoplasm, however in the blood and interstitial fluid too. Here, it is present at the levels of 4060 ng.mL-1 and does not represent any signal for cells of the immune system.However, a damage of tissues or organs changes a situation. Uric acid is released out of cells and a local microenvironment around dying cells becomes over-saturated what results in its crystallisation.
10. Uric acid as an alarminContrary to native uric acid, its microcrystals are already stimulatory. After being engulfed by macrophages, they are recognized by cytoplasmic PRRs, which subsequently induce inflammatory processes; so they act as alarmins.There are various cytoplasmic PRRs. Those recognizing uric acid microcrystals are NLRP3 (cryopyrin).
11. NLRP3NLRP3 consists of 4 domains:the 1st one, LRR, recognizes a ligandthe 2nd and 3rd domains are involved in oligodimerization the 4th (PYD) interacts with an adaptor molecule – ASCNat Rev Immunol 12010; 10: 210-5
12. After ligand recognition, NLRP3 oligomerizesASC binds to its PYD domainASC subsequently recruits pro-caspase 1All three molecules (i.e. NLRP3, ASC, and pro-caspase) form one unit, called inflammasomeNat Rev Immunol 2010; 10(5): 293
13. Pro-caspase 1 binding to NLRP3 results in its conversion to active caspase 1.It targets inactive pro-IL-1β (pro-IL-18) and converts it to active cytokine, which is released out of the cells and mediates its proinflammatory function.Nat Rev Immunol 2010; 10(5): 293
14. Nat Rev Immunol 2010; 10: 210-5
15. Nature Rev Immunol. 2010; 10: 293NLRP3 and other PRRs can be activated not only by DAMPs, however also spontaneously when there is a breakdown in their structure Autoinflamatory diseases(Periodic fevers)
16. Autoinflammatory diseasesAutoinflammatory diseases constitute a group of genetic disorders whose main clinical features are recurrent episodes of inflammatory lesions that can affect the skin, joints, bones, eyes, gastrointestinal tract, and nervous system in association with signs of systemic inflammation.Underlying nature of autoinflammatory diseases is in mutations of genes coding for some PRRs, those coding for some cytokine receptors or regulatory proteins.
17. Autoiinflammatory dis. Autoimmune dis.Chronic activation of the immune systemMechanisms of innate imm. Mechanisms of innate imm. Mechanisms of adaptive im. Inflammation and tissue injury
18. FMF is caused by mutations in the MEFV gene, which encodes the protein pyrin, primarily expressed in peripheral blood leucocytes, especially neutrophils and monocytes Pyrin is a member of the pyrin-domain (PYD) containing proteins, which are able to bind to the PYD domain of other proteins, including adaptor molecule ASCFamiliar Mediterranean fever Rich RR et al., Clin Immunol 2019 The gain-of-function mutations in the MEFV gene render pyrin hyperactive
19. Binding of pyrin to ASC results in its activation with consequent recruitment and activation of procaspase 1 caspase 1 activation of pro-IL1β overproduction of IL1β inflammationFamiliar Mediterranean fever Buc M. Autoimunita 2016
20. Familiar Mediterranean fever FMF is AR disease. Over 90% of patients become symptomatic within the first two decades of life. Typically, attacks are characterized by abrupt onset of high fever, peaking soon after onset and lasting for 12 hours to 3 days. Subsequently, the fever subsides rapidly. Painful serositis accompanies the fever. Over 95% of patients experience abdominal pain, which lasts up to 3 days; it is caused by sterile peritonitis
21. Familiar Mediterranean fever Synovitis with monoarthritis of knee, ankle, or wrist occurs in one-half to three-quarters of patients. The skin can be affected. Erysipelas-like skin lesions overlying the shins are very characteristic of FMF but are only seen in 30% of patients.Less frequent symptoms of FMF include vasculitis, orchitis, aseptic meningitis, and myalgia.Attack frequency varies greatly among patients and during an individual patient’s life. Attacks may be as frequent as 2–3 times each month and as rare as less than once a year.
22. CRYOPATHIESMutation in NLRP3 (= cryopyrin)NLRP3 receptor oligomerizes and activates itself without binding of a ligand non interrupting, continuing, synthesis of IL-1β by macrophages – its levels increase from physiological 6 ng.L-1 to up 30 ng.L-1 and more systemic inflammation
23. Systemic inflammation manifests itself by fever, tiredness, loss of energy, myalgias; amyloidosis develops. In children – a growth retardation. Subsequently, symptoms characteristic for a particular disease develop. These disorders are generally known under the term CAPS (Cryopyrin associated periodic syndromes):Familiar cold autoinflammatory syndromeMuckle-Wells syndromeNOMID/CINCA syndrome
24. Amyloidosis 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.Classic facial features of amyloidosis with bleeding under the skin around the eyes.
25. DIRA syndrome Deficiency of the IL-1 receptor antagonist
26. IL-1βBy acting on the hypothalamus, IL-1β increases a temperature, supports a sleepiness, and a loss of appetiteIL-1β stimulates the liver increase of APPs synthesisIL-1β is a chemotactic factor for neutrophilsGoldsby et al.: Kuby Immunology 4th ed., 2000
27. IL-1 receptor antagonistActivity of IL-1β is controlled by IL-1Ra.IL-1β mediates its function by binding to its two chains receptor; IL-1β binds to both chains.IL-1Ra binds to one chain of IL-1β receptor only no activation of the cell.Under physiological state, there is equilibrium between activities of IL-1 and IL-1Ra. Buc M, Imunológia 2012
28. DIRA syndrome (Deficiency of IL-1R antagonist) Mutations within the gene (IL1RN; 2q), which encodes IL-1β receptor antagonistDIRA syndrome manifests itself by affecting skin (pustulosis, pyderma gangrenosum) and bones (osteomyelitis)
29. Anakinra a recombinant version of IL-1 receptor antagonist Rilonacept a fusion protein of IL-1Ra with IgG1Canakinumab anti IL-1β monoclonal antibodyBiological therapy of CAPS and DIRADrug Safety 2015; 38(5): 455-79RILONACEPT
30. TRAPSTNF receptor associated periodic syndromeTRAPS is an autosomal dominant autoinflammatory disease It results from mutations within the gene (NFRSF1A; 12p13) encoding TNFR1 (p55)
31. Two forms of TNF-receptors: p55 = TNFR1 p75 = TNFR2Most TNF activities are mediated by its binding to TNFR1TNFR1 exists either as membrane-bound or solublesTNFR1 neutralizes plasma TNF and so regulates its levels and activitiesAbbas K et al. Immunology 2012
32. 1) TNF binds to the TNF receptor (p55) on the surface of inflammatory cells2) After receptor triggering, TNFR1–associated death domain (TRADD) is recruited, inducing a signalling cascade leading to apoptosis and production of proinflammatory cytokines 3) Receptors are also shed from the surface, leading to a pool of receptors that dampen immune responses (4) TNF signallingRich RR et al., Clin Immunol 2019
33. Mutated TNF receptors form aggregates and are retained intracellularly These aggregated receptors are capable of binding TRADD (5) and stimulate ligand-independent cytokine production inflammation (systemic pathological effects)TRAPSRich RR et al., Clin Immunol 2019
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35. Clinical symptomsTRAPS is characterized by recurrent attacks of fever, abdominal pain, migratory rash, myalgia, periorbital oedema, and internal inflammatory manifestations (serositis /pericarditis, pleuritis, peritonitis/ fasciitis).Attacks are typically of several days to six weeks in duration and often start in early childhood. TRAPS patients are also susceptible to the development of potentially fatal amyloidosis (10% of patients).
36. The treatment of TRAPS patients by anti TNF monoclonal antibodies is not effective, however by etanercept is. (Et. = a fusion protein of p75 with IgG1) The treatment of TRAPS patients IgG1Etanercept Safety Review March 4, 2003.
37. There are more autoinflammatory diseases as those shown in previous families. They are listed in the slide that follows.More details about them can be found in articles and textbooks
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