Autoinflammatory diseases Buc M Antigen recognition by adaptive

Autoinflammatory diseases Buc M

Antigen recognition by adaptive immunity B and T cells express specific receptors that are able to recognize 109 till 1012 various antigens Nat Rev Immunol

Antigen recognition innate immunity Innate 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).

Trinity of the most important PRRs Trends Immunol Ø TLRs – recognize all type of germs Ø NLRs – recognize bacteria Ø RLRs – recognize viruses 4

Abbas K et al. Immunology 2018

Alarmins and DAMPs Ø 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. Ø Humans can also be damaged by drugs, such as chemotherapeutics, which kill tumour cells, however they may damage also healthy cells. Ø 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)

Pathogen-Associated Molecular Patterns Nucleic acids Proteins ss. RNA Viruses ds. RNA Viruses Cp. G Viruses, bacteria Pilin Bacteria Flagellin Bacteria LPS Gram-negative bacteria Lipoteichoic acid Gram-positive bacteria Mannan Fungi, bacteria Glucans Fungi Cell wall lipids Carbohydrates

Alarmins Stress-induced proteins Crystals HSPs Proteolytically cleaved extracellular matrix Proteoglycan peptides Monosodium urate Mitochondria and Formylated peptides mitochon. components and ATP Nuclear proteins HMGB 1, histones Cytokines Il-1

Uric acid as an alarmin Uric acid is present not only in the cytoplasm, however in the blood and interstitial fluid too. Here, it is present at the levels of 40 60 ng. m. L-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.

Uric acid as an alarmin Contrary 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 NLRP 3 (cryopyrin).

NLRP 3 consists of 4 domains: Nat Rev Immunol 12010; 10: 210 -5 Ø the 1 st one, LRR, recognizes a ligand Ø the 2 nd and 3 rd domains are involved in oligodimerization Ø the 4 th (PYD) interacts with an adaptor molecule – ASC

Nat Rev Immunol 2010; 10(5): 293 Ø After ligand recognition, NLRP 3 oligomerizes Ø ASC binds to its PYD domain Ø ASC subsequently recruits pro-caspase 1 Ø All three molecules (i. e. NLRP 3, ASC, and pro-caspase) form one unit, called inflammasome

Pro-caspase 1 binding to NLRP 3 results in its conversion to active caspase 1. Nat Rev Immunol 2010; 10(5): 293 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: 210 -5

NLRP 3 and other PRRs can be activated not only by DAMPs, however also spontaneously when there is a breakdown in their structure Nature Rev Immunol. 2010; 10: 293 Autoinflamatory diseases (Periodic fevers)

Autoinflammatory 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.

Autoiinflammatory dis. Autoimmune dis. Chronic activation of the immune system Mechanisms of innate imm. Mechanisms of adaptive im. Inflammation and tissue injury

Familiar Mediterranean fever Rich RR et al. , Clin Immunol 2019 The gain-of-function mutations in the MEFV gene render pyrin hyperactive 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 ASC

Familiar Mediterranean fever Binding of pyrin to ASC results in its activation with consequent recruitment and activation of procaspase 1 activation of pro-IL 1β overproduction of IL 1β inflammation Buc M. Autoimunita 2016

Familiar Mediterranean fever Ø FMF is AR disease. Over 90% of patients become symptomatic within the first two decades of life. Ø 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. Ø Painful serositis accompanies the fever. Ø Over 95% of patients experience abdominal pain, which lasts up to 3 days; it is caused by sterile peritonitis

Familiar Mediterranean fever Ø Synovitis with monoarthritis of knee, ankle, or wrist occurs in one-half to three-quarters of patients. Ø 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. Ø Less frequent symptoms of FMF include vasculitis, orchitis, aseptic meningitis, and myalgia. Ø 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.

CRYOPATHIES Mutation in NLRP 3 (= cryopyrin) NLRP 3 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

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) yndromes : Familiar cold autoinflammatory syndrome Muckle-Wells syndrome NOMID/CINCA syndrome

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.

DIRA syndrome Deficiency of the IL-1 receptor antagonist

IL-1β By acting on the hypothalamus, IL-1β increases a temperature, supports a sleepiness, and a loss of appetite IL-1β stimulates the liver increase of APPs synthesis Goldsby et al. : Kuby Immunology 4 th ed. , 2000 IL-1β is a chemotactic factor for neutrophils

IL-1 receptor antagonist Activity of IL-1β is controlled by IL-1 Ra. IL-1β mediates its function by binding to its two chains receptor; IL-1β binds to both chains. IL-1 Ra binds to one chain of IL-1β receptor only no activation of the cell. Buc M, Imunológia 2012 Under physiological state, there is equilibrium between activities of IL-1 and IL-1 Ra.

DIRA syndrome (Deficiency of IL-1 R antagonist) Mutations within the gene (IL 1 RN; 2 q), which encodes IL-1β receptor antagonist DIRA syndrome manifests itself by affecting skin (pustulosis, pyderma gangrenosum) and bones (osteomyelitis)

Biological therapy of CAPS and DIRA RILONACEPT Anakinra a recombinant version of IL-1 receptor antagonist Rilonacept a fusion protein of IL-1 Ra with Ig. G 1 Drug Safety 2015; 38(5): 455 -79 Canakinumab anti IL-1β monoclonal antibody

TRAPS TNF receptor associated periodic syndrome TRAPS is an autosomal dominant autoinflammatory disease It results from mutations within the gene (NFRSF 1 A; 12 p 13) encoding TNFR 1 (p 55)

Two forms of TNF-receptors: p 55 = TNFR 1 p 75 = TNFR 2 Most TNF activities are mediated by its binding to TNFR 1 exists either as membrane-bound or soluble s. TNFR 1 neutralizes plasma TNF and so regulates its levels and activities Abbas K et al. Immunology 2012

TNF signalling 1) TNF binds to the TNF receptor (p 55) on the surface of inflammatory cells 2) After receptor triggering, TNFR 1–associated death domain (TRADD) is recruited, inducing a signalling cascade leading to apoptosis and production of proinflammatory cytokines Rich RR et al. , Clin Immunol 2019 3) Receptors are also shed from the surface, leading to a pool of receptors that dampen immune responses (4)

TRAPS Mutated TNF receptors form aggregates and are retained intracellularly Rich RR et al. , Clin Immunol 2019 These aggregated receptors are capable of binding TRADD (5) and stimulate ligand-independent cytokine production inflammation (systemic pathological effects)

Clinical symptoms TRAPS 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).

The treatment of TRAPS patients Ig. G 1 Etanercept Safety Review March 4, 2003. The treatment of TRAPS patients by anti TNF monoclonal antibodies is not effective, however by etanercept is. (Et. = a fusion protein of p 75 with Ig. G 1)

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