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Inflammasomes and dermatology*

Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.


THE INFLAMMASOME
Inflammasomes, first described in 2002, are intracellular multiprotein complexes consisting of three elements: a molecular pattern recognition receptor (PRR), an apoptosis-associated specklike protein containing a caspase-recruitment domain (ASC) adaptor protein, and a caspase-1 enzyme. 1,2 Inflammasomes are constitutive of the innate immune system, and are responsible for regulating the immunological response to several stimuli, whether exogenous, such as bacterial agents, or endogenous, such as neoplasia, by means of cytokine production and secretion. Inflammasome assembly and activation are triggered by the recognition of stimuli by PPR receptors, which interact with the ASC adaptor molecule. ASC protein is then linked to the procaspase-1, which is then cleaved, activating caspase-1. Activation of caspase-1 culminates in the cleavage of pro-IL-1β and pro-IL18, resulting in their active forms IL-1β and IL18, respectively, which stimulate the inflammatory response. 2,3,4 The activation of capase-1 through the inflammasome pathway is also capable of inducing pyroptosis, a type of inflammatory cell death. 5,6 Inflammasomes are named in accordance with their intracellular receptor's nomenclature. Two receptor classes have already been identified: NLR-Nod like receptors, and ALR-AIM2-like receptors. At least 6 types of inflammasomes have been described: NLRP1, NLRP3, NLRP6, NLRP12, NLRC4/IPAF, and AIM-2. The first five are NLR receptors, whereas AIM-2 is an ALR receptor. 4,7 Normal inflammasome function, with IL18 and especially IL-1β, synthesis, is required for the innate immune system to act effectively against pathogens (virus, fungi, and bacteria) and against other diseases, including some types of cancer. When its activity becomes excessive, deleterious effects may occur in the organism.
Since their definition, inflammasome disorders have been implicated in several pathologies, becoming a possible target for therapeutic action. 8 Hereditary fever syndromes represented the group of diseases initially associated with inflammasomes. 9 In addition to these, other syndromes have recently had their physiopathogenesis associated with inflammasomes, such as: metabolic diseases (type 2 diabetes, obesity, arteriosclerosis), 10 neurological disorders (Alzheimer's, multiple sclerosis), 11,12 autoimmune diseases (vitiligo, rheumatoid arthritis, type 1 diabetes, Addison's disease, lupus erythematosus), 13,14 infections (HIV, Francisella tularensis, Legionella pneumophila, Listeria monocytogenes, Mycobacterium tuberculosis, varicella zoster virus, S. pneumoniae), 15,16,17,18,19,20 and neoplasia (gastric, hepatic, colorectal, breast, and melanoma). 21,22 2. AUTOINFLAMMATION VS. AUTOIMMUNITY When we speak of autoimmune diseases, we refer to adaptive immune disorders, involving inflammatory diseases with aberrant responses to autoantigens, controlled by B cells and T cells, with the presence of autoantibodies. 23 The concept of autoinflammatory disease first appeared in 1999 and gained strength after the inflammasome was defined in 2002. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune system cells, such as macrophages, neutrophils, mast cells and NK cells, resulting in tissue damage in the absence of autoantigens and autoantibodies.
Since then, several diseases, previously described as autoimmune, or not fitting any classifications, have been classified as autoinflammatory, or, at least, as having an autoinflammatory component in their physiopathogenesis. Some pathologies share autoimmune and autoinflammatory characteristics. 23,24,25 We will provide here a literature review on skin diseases associated with inflammasomes.

MONOGENIC AUTOINFLAMMATORY DISEASES
Monogenic autoinflammatory diseases constitute a group of rare hereditary syndromes that lead to exacerbated responses by the innate immune system and present some common characteristics among them: recurrent signs of systemic inflammation, such as fevers, with early onset in childhood; heredity, in many cases; and frequent skin manifestations. Among these diseases, inflammasomopathies represent the most important group, and will be described below. 26,27

1-CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS)
Cryopyrin-associated periodic syndromes (CAPS) include three rare entities that form a spectrum: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease. These syndromes result from mutations in tbe NLRP3 gene and in the 1q44 chromosome, with dominant autosomal inheritance and variable penetrance, but with some new mutation cases, especially in the syndrome's more serious spectrum. 26,28,29,30 Over 90 mutations have been reported. 31 This disease's physiopathology is characterized by excessive IL-1β production by macrophages, monocytes, and chondrocytes. 32 In an animal model, Nakamura and Kambe demonstrated that dermis mast cells produced histamine, as well as IL-1β, and are mainly responsible for the production of this cytokine. 33 Manifestations tend to accompany patients throughout their lives, and prognosis depends mainly on the development of secondary amyloidosis, which predominantly affects the kidneys. 34 Familial cold autoinflammatory syndrome, previously called familial cold urticaria, is the least severe form, beginning in the first months of life, with maculopapular or urticarial, usually not pruriginous, lesions that may be painful, associated with fever, chills, myalgia, headaches, arthralgia, and conjunctivitis. 28,29,32 Histopathology of lesions evinces a sparse neutrophil infiltrate in the reticular dermis, which may be perivascular or perieccrine. 35 Episodes, which tend to be less than 12 hours long, may be triggered by low ambient temperatures. However, local exposures to ice do not trigger the outbreak of lesions, which is different from that which occurs with urticaria and non-familial cold lesions. 28,29,32 The mechanism through which the cold triggers the lesions is unknown. Secondary amyloidosis is rare, and the prognosis regarding afterlife is usually good. 28,29 Muckle Wells syndrome presents the same characteristics as the familial cold autoinflammatory syndrome, as well as sensorineural hearing loss during adolescence. In addition, outbreaks may last longer (between 12 and 36 hours). Secondary amyloidosis may occur in up to 25% of the cases. 28,29,32 Hence, no association can be drawn between the ambient temperature and the manner in which the outbreaks are triggered. 29 The most severe form of CAPS is called neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous, and articular syndrome (CINCA).
It manifests itself as high fever episodes with maculopapular or urticarial lesions, with persistent exanthema, arthritis, lymphadenopathy, hepatosplenomegaly, and chronic meningitis. It is associated with late physical and mental development, sensorineural hearing loss, and a loss of vision. Exaggerated patella and distal femur osteocartiloginous growth is characteristic, and facial deformities, such as flattened nose tip, macrocephaly, frontal bossing, and protruding eyes, may also occur. 26,28,29 The revolution in treatment took place with the introduction of the IL1 receptor antagonist, Anakinra. Response to treatment is usually good, with rapid improvements in the outbreaks. If started early, treatment improves the prognosis as regards the development of sequelae and its evolution into amyloidosis. Two other medications, Rilonacept, a dimeric fusion protein, and Canakinumab, a human monoclonal anti-IL-1β antibody, are other therapeutic options. 29 Clinically, these syndromes appear in recurrent sterile arthritis in early childhood, which may progress with deformities.
Pyoderma gangrenosum lesions occur mainly on the distal portion of one's limbs, but cases with multiple disseminate lesions have also been reported. Skin abscesses may also occur. Cystic acne and hidradenitis occur during adolescence. 29,30 The therapeutic response has varied in previosly reported cases, with IL-1 inhibitors being more effective to combat articular symptoms, and anti-TNF being more effective for skin conditions. 30

5-SCHNITZLER SYNDROME
Classification of this syndrome as an autoinflammatory disease is still controversial. Some cases have been associated with autosomal dominant mutations on the NLRP3 gene, which could place it within the CAPS group, whereas, in other patients, this mutation has not been found. 29,46,47 The presence of monoclonal gammopathy by IgM and the typical skin condition of a neutrophilic urticarial dermatosis are essential for the diagnosis, associated with at least two of the following criteria: arthralgia or arthritis, bone pain, palpable lymph nodes, hepatic or splenomegaly, increased erythrocyte sedimentation rate (ESR), leukocytosis, and abnormal findings in bone morphological investigations. Typical dermatological lesions ( Figure 1) are usually the first symptom and are characterized by macules, papules, or erythematous plaques, with little or no prurigo, which disappear within hours and do not leave scars. 48

6-DEFICIENCY OF THE IL-1 RECEPTOR ANTAGONIST (DIRA)
This disease was first described in 2009 in nine patients who had presented sterile multifocal osteomyelitis, periostitis, and pustulosis since the neonatal period, but without fever. The patients presented a homozygotic mutation of the IL1 receptor antagonist (IL1RA). 49 The lack of opposition to IL-1 signaling leads to a severe In a case series of 22 patients with autoinflammatory diseases associated with the mutation of the NLRP3 inflammasome, one of these patients was diagnosed with associated Sweet's syndrome. 53 In two case reports of patients diagnosed with Sweet's syndrome, and who had been unaffected by various therapies, improvement was observed after treatment with Anakinra, an IL1RA, which is the medication of choice for CAPS and other autoinflammatory diseases. 54,55 Mutations in the PSTPIP1 gene, the same associated with PAPA syndrome, were identified in patients with isolated pyoderma gangrenosum. 56 Wallach, who in 1991 proposed criteria for the classification of neutrophilic dermatoses, in 2015 suggested the hypothesis that the neutrophilic dermatoses would represent the cutaneous expression of autoinflammation. 52

PSORIASIS
The classification of psoriasis as an autoimmune disease itself presents limited evidence 57  in an analogous mechanism, which occurred in autoinflammatory diseases stemming from the mutation of NLRP3 inflammasome.
These authors suggest that these haplotypes of NLRP1 would be insuficiente to unleash the disease, but they could act as adjuvants.
The increased production of IL-1β can contribute to the pathogenesis of autoimmunity to facilitate the presentation of autoantigens. 69 In

LUPUS ERYTHEMATOSUS
The participation of the inflammasome on the physiopathogenesis of systemic lupus erythematosus (SLE) has been a target of Behcet's disease study in recent years. Two NLRP1 single nucleotide polymorphisms were associated with SLE, mainly with the development of nephritis, cutaneous lesions, and arthritis. NLRP3, AIM2, NLRC4, and caspase-1 polymorphisms showed not direct correlation. 14 In another study, evaluating SLEs that begin in childhood and adolescence, a relationship was found with the IL-1β polymorphism but not with NLRP1. 72 The relationship between IL-1β polymorphisms and the development of SLE has produced conflicting results in the literature. 73 By contrast, IL-18 polymorphisms have proven to be associated with the risk of the development of the disease. 74 The most reliable piece of evidence of the relationship between SLE and inflammasomes was found in lupus nephritis. As regards skin involvement, it is known that IL-18 seems to play an important role, as it presents an increased expression in the keratinocytes of patients with cutaneous lupus. 75 79 One better expression of the NLRP3 and AIM2 genes was observed in another study in which the caspase-1 activity was also correlated with the synthesis of IL-1β and IL-18, coupled with the development of fibrosis. 80

ACNE
Acne is a chronic inflammatory disease of the pilosebaceous unit, with four well-defined pathogenic factors: abnormal keratinization, excessive sebaceous production, colonization by Propionibacterium acnes, and inflammation. However, the sequence in which such events occur is still controversial. Some have postulated the possibility of an inflammation being the initial factor, by means of Toll-like 2 receptors and P. acnes inflammasomes, thus changing the hypothesis in which the intial point of the disease would be the abnormal keratinization with a microcomedone formation. All cases of acne would, therefore, be truly inflammatory. 81  A reduction in the expression of the ASC protein and of the IL-18 was observed, a finding that the authors suggest to be a possible explanation for the loss of microbial homeostasis. 85 The participation of inflammasomes was also suggested due to the synthesis of IL-1β by the keratinocytes stimulated by UVB radiation. IL1RAs can be useful in cases of contact dermatitis.

ATOPIC DERMATITIS
The role of inflammasomes has been debated in the etiopathogenesis of atopic dermatitis. It is believed that the activation of inflammasomes by allergens or pathogens can lead to an exacerbation of the disease. 93

SKIN CANCER
The association between an inflammatory response and cancer continues to be controversial, and studies have shown the role of the activation of inflammasomes in tumorigenesis, both as a protective factor as will as a stimulating factor,

SQUAMOUS CELL CARCINOMA (SCC)
Drexler et al., in a study with mice, showed that the ASC protein would have a pro-inflammatory role in the tumor inflammatory infiltrate cells, in turn favoring the development of SCC, but with a contrary effect on the keratinocytes, acting as a tumor suppressor.
In this same work, the loss of ASC expression in the SCC lesions in human tissues was observed. 97 In one study conducted with SCC

INFECTIONS
The immediate response of the body against pathogens is given by the innate imune system, with the activation of the innate response regulating the prompting of the adaptive immune reponse. The understanding of the host response against infection has changed in recent years due to studies evaluating the role of inflammasomes. 106

FUNGI
The fungi of the Malassezia genus are skin commensals, but are also involved in some skin diseases. Kistowska et al. showed that different species of Malassezia present the potential to activate the NLRP3 inflammasome in antigen-presenting cells, leading to a high synthesis of IL-1β. 107 The NLRP3 and NLRC4 inflammasomes play key roles in the innate response against mucosal infections, as reported by Candida in two published studies. 108,109 In addition, the activation of inflammasomes seems to depend on the transformation from a yeast form to a filamentous form. 110,111 The relevant function of the

NLRP3 inflammasome in the defense against infection caused by
Microsporum canis and Trichophyton schoenleinii was also verified. 112,113 In one recently published study conducted with mice, the par- Different from that observed with NLRP3 in the infected skin, no NLRP1 expression was observed. However, the study was unable to conclude if this activation is beneficial for the host or if the propagation of the virus is necessary. 115 The role of the inflammasome in the response to infection by HPV-16 in keratinocytes was investigated, demonstrating the prompting of the formation of the AIM2 inflammasome, with a consequent synthesis of IL-1β. A possible pathway is being discussed in an attempt to understand the reason why the HPV infection persists in some individuals. 116 Differently from the intracytoplasmatic receptors (NLRP1, NLRP3, NLRC4, and AIM2), the IFI16 is an intranuclear pattern recognition receptor that proved to be capable of recognizing the herpes virus associated with Kaposi's sarcoma (HVSK), leading to the activation of the IFI16 inflammasome, with the synthesis of IL-1β. 117 Johnson et al. demonstrated that the type 1 herpes virus (HSV-1) activates the NLRP3 and IFI16 inflammasomes during the intial stages of the infection and that there is no participation of the AIM2 inflammasome. However, with the progression of the infection, the HSV-1 develops mechanisms to suppress this inflammatory response. 118

BACTERIA
The relationship between the inflammasome and infection caused by Staphylococcus aureus has been studied in the literature.
One mechanism to spark the neutrophilic response against cutaneous infection was proposed. In this model, in the epidermal infection (impetigo or seconday surface infection), the response would mainly be through the synthesis of IL-1α in keratinocytes. In dermal or subcutaneous infections (cellulitis, abcess), a synthesis of IL-1β would occur by means of the inflammasome pathway, both by resident cells and by recruited tissue cells. 119 In one study conducted with mice, it was found that the neutrophilic response, essential to the formation of abscesses and the improvement of the infection, is mediated by the IL-1β and that the neutrophils themselves are the main cells responsible for the synthesis of this interleukin, through some given pathways, especially those of the NLRP3 inflammasome. 120 Nonetheless, the response associated with the inflammasome did not prove to be beneficial. The α-hemolysin, known as a bacteria virulence fator, is capable of stimulating the NLRP3 inflammasome, causing cell death. This inflammatory response on the part of the host through tissue necrosis limits the capacity of infection control. The inflammasome appears to be a possible target for future therapies against severe infections caused by S. aureus. 121 Haemophilus ducreyi is an etiological agente of a canker sore.
Although it is an agent that is predominantly extracellular, some of its components can be recognized by the inflammasome. The mRNA expression of genes associated with the inflammasomes was investigated in the infected skin, showing an increase in the NLRP3, NLRC4, AIM2, caspase-1, caspase-4, caspase-5, and IL-1β expressions, illustrating that the inflammasome can participate in the innate immune response toward this pathogen. The synthesis of IL-1β in vitro in macrophages derived from monocytes, through the NLRP3 inflammasome pathway, was also observed. 122

PROTOZOA
The true role of the inflammasone in American tegumentary leishmaniasis (ATL) is still uncertain and was recently presented for the first time in 25 patients from the city of Carte de Pedra, Bahia, Brazil, an endemic zone for Leishmania braziliensis. The profile of the genome from the lesional skin was compared to the normal skin of controls from a non-endemic area. This study found a high expression of the components of inflammasomes (IL-1β, AIM2, NLRP3, caspase-1, and caspase-5) in sick skin. This profile was observed in a similar manner both in the more recent, non-ulcerated lesions, as well as in the older, ulcerated lesions, which suggests that, shortly after the onset of the infection, the inflammatory response is triggered, which may well explain why even early treatment centers are unable to prevent this type of ulcer. 123

PRESSURE ULCER
Using a biomechanical experimental model, in which young and elderly human skin were submitted to pressure and ischemia, Stojadinovic et al. observed that the elderly skin already presented a lesser expression of the components of the inflammasome and that the pressure did not result in any changes. The synthesis of IL-1β, which was already low in the elderly skin, did not change during the study. In the young skin, the expression of NLRP3 and caspase-1, but not of the ASC adaptor protein, increased significantly with pressure. By contrast, the synthesis of IL-1β diminished, suggesting that the pressure can undo the link between the components of the inflammasome, thus reducing the quantity of IL-1β produced, even with the increased presence of these components.
It is also being debated whether or not the reduction in the innate immune response with age can be involved in the greater risk for the development of pressure ulcers . 124

WOUND HEALING
The function of the inflammasome in the skin healing process is not well-defined in the literature, but some studies have treated the subject. In one in vitro model conducted with material from mice, genetic variations of NLRP1 showed the capacity to interfere in the production of cytokines that might be involved in the healing process. 125 The NLRP3 inflammasome may well be involved in slow healing in diabetic patients, as seen in the findings from a work conducted with diabetic and obese mice in which the blocking of this inflammasome led to an improvement in the healing process. 126 In another study with material from both humans and mice, it was postulated that the NLRP3 inflammasome may be continually ac-tivated within the macrophages present in the wounds of diabetic patients, and that this contributes to the difficulty of wound healing. 127 By contrast, another study conducted with mice showed that the NLRP3 inflammasome would be important in the initial stage of the healing process. 128

DRUG REACTIONS
Weston and Uetrecht debate the role of the inflammasome in the genesis of idiosyncratic medication reactions. The majority of these reactions occur due to medication that produces reactive metabolytes. Four medications were evaluated, two of which are associated with cutaneous reactions (teleprevir and dimethyl fumarate) and two that are not related to cutaneous lesions (boceprevir and ethacrynic acid). Only the former medications were able to activate the inflammasome in monocytes of human peripheral blood. The hypothesis raised is that the capacity of the reactive metabolyte to stimulate the inflammasome would be a determining factor in the potential of a given medication to cause idiosyncratic reactions. 129 Another study proposed that the activation of the inflammasome may well be a fundamental part for the cutaneous rash that is caused by nevirapine. 130 Further study is warranted to corroborate these hypotheses.

ANDROGENETIC ALOPECIA
Evaluating the biopsies from 18 male patients, Vaccari et al. identified an increased caspase-1 expression in the epidermis of patients with untreated androgenetic alopecia (AGA), as well as in cases of AGA in which finasteride was used, but with therapeutic failure. Patients with AGA who were using finasterie with a good therapeutic response and the normal controls presented a reduced caspase-1 expression. In addition, this same study demonstrated, in a keratinocyte culture of human skin, that finasteriade, in the presence of testosterone or of di-hydrotestosterone, leads to a reduction in the levels of caspase-1. These findings suggest that the caspase-1 activity is associated with AGA and shows a possible interaction between the steroid hormones and the innate immunity, which may represent a viable future therapy for AGA. 131

CONCLUSION
Skin, the major organ of the human body, is continually exposed to a wide range of stimuli, which can be recognized by the in- Questions s 1-About inflammasomes, it is incorrect to state that: a) they are key pieces in adaptive immunity and are responsible for responses to autoantigens in autoimmune disorders. b) described for the first time in 2002, they are constitutive of the innate immune response to exogenous and endogenous stimuli. c) they are intracellular protein compounds, formed by a pattern recognition receptor, an adaptor protein, and a caspase-1 enzyme. d) activation of inflammasome complex leads to the synthesis of cytokines (IL-1β and IL18).

2-Regarding the concept of autoinflammatory disease, it is correct to state that: a)
it is an old and obsolete concept, which included diseases currently better classified as autoimmune. b) the presence of autoantigens and autoantibodies are essential to classify a pathology as autoinflammatory. c) autoinflammation and autoimmunity may coexist in a single disease, as a result of innate and adaptive immune system disorders, respectively. d) the activation of B and T cells is essential for the physiopathology of autoinflammatory diseases.

3-About cryopyrin-associated periodic syndromes (CAPS),
it is incorrect to state that: a) include a spectrum that encompasses familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease. b) result from mutations in NLRP3 inflammasome, leading to the excessive IL-1β synthesis. c) in familial cold autoinflammatory syndrome, previously called familial cold urticaria, episodes may be triggered by exposure to low ambient temperatures. d) treatment with IL1 receptor antagonist (Anakinra) provides discouraging results, and does not interfere in the disease's natural history.

5-About pyoderma gangrenous and
Sweet's syndrome, we may state that: a) the hypothesis of these being autoinflammatory diseases is rejected due to clinical and histological differences in relation to hereditary autoinflammatory diseases. b) the undefined pathogeny and the similarity to hereditary autoinflammatory diseases make way for the hypothesis that they are associated with inflammasome disorders. c) experts on the subject have declared that they are against the association between pyoderma gangrenoum and autoinflammation. d) they have definitely been associated with inflammasome gene mutations. 10-About vitiligo, it is possible to state that: a) it is a monogenic autoinflammatory disease. b) it is a typical autoimmune disease, with no evidence of innate immunity participation. c) evidence suggests the participation of innate immunity by means of the inflammasome complex in its physiopathogeny. d) Anakinra is currently the treatment of choice.

11-
The following are factors suggesting the participation of inflammasomes in the physiopathology of hidradenitis, except: a) increased IL-1β in the lesions. b) favorable response to colchicine treatment. c) greater expression of inflammasome components in the lesions. d) a condition similar to hidradenitis in PAPA syndrome.
12-Regarding eczema and inflammasome, it is incorrect to state that a) nickel may induce sensitization by means of NLRP3 inflammasome complex activation. b) innate and adaptive immunity may be part of the contact dermatitis sensitization mechanism. c) a contact allergen may stimulate IL-1β synthesis through the inflammasome pathway. d) their relation to atopic dermatitis is well documented.

13-In the skin oncology field, inflammasomes:
a) may participate in tumor genesis by means of ultraviolet radiation stimulus, leading to IL-1β synthesis. b) play a well-defined role as protector in squamous cell carcinoma. c) inflammasome activation is associated with a better prognosis in melanoma. d) it has been defined that inflammation acts as a protective factor in oncogenesis.
14-About the Anakinra drug, it is correct to state that: a) it is an IL-1 receptor antagonist. b) it is contraindicated in inflammasomepathies such as CAPS. c) it acts by reducing IL-1 synthesis. d) it acts by increasing IL-1 effect.

15-Pyroptosis is:
a) the inflammasome intracellular receptor activation mechanism. b) apoptosis induced by inflammasome activation. c) apoptosis induced by adaptive immunity, d) apoptosis induced by inflammasome inhibition. 18-Inflammasome activation represents: a) a mechanism that may be essential in fighting infections; b) a pathological mechanism, inactive in healthy individuals. c) a defense mechanism, inactive in hereditary diseases, such as familial Mediterranean fever. d) a mechanism restricted to cutaneous-mucous diseases.

19-Which of the words below is not associated with autoinflammatory diseases: a) autoantibodies b) innate immunity c) inflammasome d) neutrophils
20-About psoriasis, it is correct to state that: a) it is caused by NLRP3 gene mutation and is considered a monogenic inflammasomepathy. b) it may be classified as a systemic inflammatory disease, with the participation of innate and adaptive immune response, and shares characteristics common to autoinflammatory diseases. c) it is a classical autoimmune disease. d) neutrophilic inflammatory infiltrates and the participation of adaptive immunity are similar characteristics to those in autoinflammatory diseases.