Autoinflammatory diseases

doi:10.1016/j.berh.2008.08.009

Best Practice & Research Clinical Rheumatology

Volume 22, Issue 5, October 2008, Pages 811-829

https://doi.org/10.1016/j.berh.2008.08.009 Get rights and content

Autoinflammatory diseases (AIDs) are illnesses caused by primary dysfunction of the innate immune system. Proteins that are mutated in AIDs mediate the regulation of NFκB activation, cell apoptosis, and IL-1β secretion through cross-regulated and sometimes common signaling pathways. AIDs include a broad number of monogenic [e.g., familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), mevalonate kinase deficiency (MKD), tumor necrosis factor (TNF)-receptor-associated periodic syndrome (TRAPS)] and multifactorial (e.g., Behçet's syndrome) disorders. These conditions are characterized by recurrent attacks of fever, abdominal pain, arthritis, and cutaneous signs; these symptoms sometimes overlap, obscuring diagnosis. Distinguishing signs and the use of specific functional tests where available (e.g., in MKD) are helpful. However, some patients remain hard to manage despite the advent of new genetic tests and/or due to lack of effective treatment.

Section snippets

What are autoinflammatory diseases?

The concept of autoinflammation was created to echo that of autoimmunity (Figure 1).¹ The innate response to external or internal aggression is triggered within hours, whereas the stronger and more specific responses of acquired immunity require the development of targeted antibodies and the activation of T lymphocytes, resulting in a longer maturation. Paradoxically, although innate immunity arose first in evolution, diseases associated with this system were recognized only in the late 1990s.

Pathophysiology

Innate immunity comprises a complex cellular system developed by mammalian organisms as protection against a wide range of danger signals.³ A set of receptors detects exogenous pathogens via the components of their bacterial membrane – called pathogen-associated molecular patterns (PAMPs). The receptors also detect endogenous self-danger signals, such as toxic compounds, defective nucleic acids, or intracellular proteins (called alarmins, which are released by dead cells after tissue injury).

The expanding clinical spectrum

The somewhat wide definition of AIDs revisits the original focus on four HRFs: FMF (gene MEFV), CAPS (gene NLRP3), MKD (gene MVK), and TRAPS (gene TNFRSF1A), but fever is present in most if not all AIDs. The diagnosis of HRF has long been exclusively based on the grounds of phenotype; they are all characterized by recurrent attacks of fever and inflammation in various target organs. Renal AA amyloidosis represents the most serious long-term complication of HRF, which usually manifest as

Diagnosis issues

Differential diagnosis can be tricky because of the clinical similarities between AIDs. Specific diagnosis became possible only after the discovery of the respective genes responsible for HRF. A registry of mutations is available online at http://fmf.igh.cnrs.fr/ISSAID/infevers.⁷⁵ Many clinicians inexperienced in these diseases will prescribe numerous molecular tests, which might cloud the issue and, regrettably, delay accurate and relevant patient care. Difficulties stem first from the fact

Complex cases

Most often, the correct diagnosis can be assembled from the concurrence of clinical, biochemical, and genetic parameters. However, overlapping and atypical symptoms can confuse the diagnosis. Cases in which the criteria of several disease and/or mutated gene clusters have identified have been reported. For example, we demonstrated the higher frequency of MEFV mutations in patients with BD.⁷⁶ Other groups confirmed these data and found an association between the presence of MEFV mutations and

Promising advances in the treatment of autoinflammatory diseases

The better understanding of AIDs pathophysiology, notably through the discovery that most of them involved alteration of cytokine regulation, marked a milestone for the care of these patients. The first successful biotherapy administered in AIDs patient was the use of anti-TNF (etanercept) in a young TRAPS patient with renal amyloidosis.⁸⁰ However, this therapy was later revealed not to be effective in all patients. Anti-TNF was also beneficial in HIDS⁸¹, PAPA⁸², Behçet's uveitis⁸³, and in

Conclusions

Whereas initial interest in FMF and related diseases was for a long time confined to specialists, the fact that most mutations are in proteins (where identified), which are key actors in the innate immunity system, recently attracted the attention of laboratories more generally interested in cell biology. The impact of this intensive research has revealed itself as being outstanding, both from a clinical and from a fundamental point of view. The general scheme that emerges from a compilation of

Summary

The study of AIDs has progressed in the last few years from the clinical characterization of the various disorders to the better understanding of the common pathways and mediators of apoptosis, inflammation, and cytokine signaling. Knowledge of the defective steps in AIDs has already resulted in the elucidation of the mechanisms of action of existing drugs and might allow the development of new therapies. In light of the promising results already achieved from newly developed treatments,

Conflict of interest statement

None declared.

Acknowledgements

This work was supported by the Centre Hospitalo-Universitaire de Montpellier and the Centre Hospitalo-Universitaire du Kremlin-Bicêtre.

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Cited by (116)

MEFV gene allele frequency and genotype distribution in 3230 patients’ analyses by next generation sequencing methods
2022, Gene
Familial Mediterranean Fever (FMF, OMIM ID: 249100) is the most common autoinflammatory, autosomal recessive disease caused by mutations in the MEFV gene. It is widespread in the Mediterranean, primarily among Turkish, Armenian, Arab and Jewish. This study aims to examine genotype distributions of common MEFV variants in the Turkish population using targeted NGS and to evaluate all rare mutations. It included 3230 people applying to Ege University Children's Hospital Molecular Medicine Laboratory with the suspicion of autoinflammatory disease between 2017 and 2021.
MEFV missense variant was detected in 1839 (56.9%) individuals. One or more mutations were found in them. 1063 patients were heterozygous (57.8%), 410 were compound heterozygous (22.3%), 238 were complex genotype (12.9%), and 128 were homozygous (7%). 56 different mutations and 141 genotypes were detected, two of which were novel (p.His87Arg, c.260A > G and p.Leu396Phe, c.1186C > T). These were determined as 6benign, 40 uncertain significant, 3 likely pathogenic and 7 pathogenic according to the ACMG classification. The most common ones were R202Q (n = 1097, 37.48%), E148Q (n = 512, 17.49%), M694V (n = 493, 16.84%), V726A (n = 155, 5.30%), M680I (n = 150, 5.12%), P369S (n = 108, 3.69%), R408Q (n = 95, 3.25%) respectively. They constitute 89.17 % of the entire patient population.
In conclusion, DNA variants/mutations in the MEFV gene were evaluated in 3230 patients. To date, no mutation screening has been encountered in such a large population using NGS. Genotype distributions of both common and rare mutations were revealed. The obtained data will hopefully contribute to the future genotype-phenotype studies of FMF disease.
Water extract of Artemisia scoparia Waldst. & Kitam suppresses LPS-induced cytokine production and NLRP3 inflammasome activation in macrophages and alleviates carrageenan-induced acute inflammation in mice
2021, Journal of Ethnopharmacology
Artemisia scoparia Waldst. & Kitam (A. scoparia) is a perennial herbal plant that is widely used as a folk remedy in Asian countries. Several studies have demonstrated that A. scoparia has various physiological effects, including anti-inflammation, anti-hypertension, anti-obesity, anti-hepatotoxicity, and anti-oxidant effects.
Aim of the study: The objective of the present study was to examine the anti-inflammatory effects of water extract of A. scoparia (WAS).
Murine bone marrow-derived macrophages (BMDMs), human monocyte THP-1 and murine fibroblast 3T3-L1 cells were used for the in vitro experiments. Cell viability and cytokine production were determined by the MTT assay and ELISA, respectively. RT-PCR was performed to determine iNOS gene expression and the Griess reaction was used to measure nitrite levels. iNOS protein expression, activation of NF-κB and MAPKs, and cleavage of caspase-1 and IL-1β were determined by Western blot analysis. A carrageenan-induced mouse model of acute inflammation was used in the in vivo experiments.
Pretreatment with WAS concentration-dependently suppressed gene expression and IL-6, TNF-α, CXCL1 and iNOS protein levels in BMDMs stimulated with LPS. In addition, pretreatment with WAS inhibited LPS-induced production of IL-6 and TNF-α in THP-1 cells and CXCL1 in 3T3-L1. Furthermore, LPS induced phosphorylation of p65 in BMDMs, and this induction was dramatically suppressed by WAS pretreatment. We further investigated whether WAS regulates activation of the NLRP3 inflammasome, which is known to be essential for IL-1β processing. WAS inhibited the production of IL-1β, but not IL-6, in response to adenosine triphosphate (ATP) and monosodium uric acid (MSU) crystals in LPS-primed BMDMs. Cleavage of caspase-1 and IL-1β was also reduced by WAS. We finally evaluated the in vivo anti-inflammatory effects of WAS in a mouse model of carrageenan-induced acute inflammation. Subcutaneous administration of WAS reduced production of the inflammatory cytokines IL-6, TNF-α, CXCL1, and IL-1β. Recruitment of immune cells, mostly neutrophils, was also reduced by administration of WAS. Infiltration of inflammatory cells and edema in the submucosa of air pouch tissues were markedly improved in the WAS-treated groups.
Our results indicate that WAS possesses potent anti-inflammatory properties. These findings suggest that A. scoparia is a candidate functional food targeting several inflammatory diseases.
Autoinflammatory disorders
2021, Inborn Errors of Immunity: A Practical Guide
Autoinflammatory syndromes, also called periodic fever syndromes, are a newly identified group of distinct hereditable disorders characterized by recurrent episodes of fever and unprovoked inflammation most commonly in skin, joints, gut, and eye. The absence of a high titer of autoantibodies or autoreactive T cells is the hallmark of autoinflammatory disorders. High frequency of inflammation in autoinflammatory diseases is mediated predominantly by the cells and molecules of the innate immune system, usually in patients with a significant genetic predisposition. It was suggested that correct diagnosis and treatment of monogenic autoinflammatory diseases rely on the physicians’ awareness. Therefore understanding of the underlying pathogenic mechanisms facilitated significant progress in the patient management.
Spectrum of the neurologic manifestations in childhood-onset cryopyrin-associated periodic syndrome
2019, European Journal of Paediatric Neurology
Neurologic complications of chronic infantile neurologic, cutaneous and articular syndrome (CINCA) are well-known, whereas there are scarce data regarding neurologic features of milder cryopyrin-associated periodic syndrome (CAPS) phenotypes. We aimed to review the neurologic features in detail and summarize the other CAPS-related manifestations in 12 children.
All children with CAPS that have been followed-up from pediatric rheumatology outpatient clinic, were enrolled to the study. In addition to the neurologic examination, magnetic resonance imaging (MRI) of brain, electroencephalography, eye examination, hearing test and intellectual assessment were done. Demographic, clinical features, genetic analysis and laboratory tests were noted from patient records and hospital database.
The median age of the subjects was 7 years (range 2–19 years), with a female-to-male ratio 2/1. The phenotype was consistent with familial cold autoinflammatory syndrome in 7 patients, Muckle–Wells syndrome in 3 patients and chronic infantile neurologic, cutaneous and articular syndrome in 2 patients. Most frequently noted neurologic clinical manifestation during the entire disease course was headache (n = 4/12) followed by seizures (n = 3/12), papilledema (n = 3/12), intellectual disability (n = 2/12), aseptic meningitis (n = 2/12), hearing loss (n = 2/12) and optic atrophy (n = 1/12). MRI of the brain revealed abnormal lesions in two patients. Uveitis or conjunctivitis were seen in two children. Overall, neurological involvement was detected in 6/12 of our cohort, of which half (n = 3) was in severe form.
Half of the children with CAPS exhibited neurologic manifestations with varying degrees of severity. Increased understanding and awareness of this rare but treatable syndrome among neurologists is essential. If remains untreated and unrecognized, this autoinflammatory syndrome could lead to significant morbidity and mortality. Besides complete resolution of systemic symptoms, anti-interleukin-1 treatment may also prevent progression of neurologic findings when initiated in the early stage of the disease.
Prolonged, Recurrent, and Periodic Fever Syndromes
2018, Principles and Practice of Pediatric Infectious Diseases
Deciphering the host genetic factors conferring susceptibility to severe COVID-19 using exome sequencing
2024, Genes and Immunity

View all citing articles on Scopus

View full text

3Autoinflammatory diseases

Section snippets

What are autoinflammatory diseases?

Pathophysiology

The expanding clinical spectrum

Diagnosis issues

Complex cases

Promising advances in the treatment of autoinflammatory diseases

Conclusions

Summary

Conflict of interest statement

Acknowledgements

Trends in Immunology

Trends in Immunology

American Journal of Human Genetics

Molecular Cell

Immunity

Cell

Biochemical and Biophysical Research Communications

Cell

Experimental Cell Research

American Journal of Human Genetics

Biochimica Et Biophysica Acta

Seminars in Arthritis and Rheumatism

The Journal of Pediatrics

Lancet

Blood

Blood

The autoinflammatory syndromes

Current Opinion in Allergy and Clinical Immunology

The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations

Current Opinion in Rheumatology

The systemic autoinflammatory diseases: inborn errors of the innate immune system

Current Topics in Microbiology and Immunology

DAMPs, PAMPs and alarmins: all we need to know about danger

Journal of Leukocyte Biology

Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen

PLoS pathogens

Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome

Nature Genetics

A candidate gene for familial Mediterranean fever

Nature Genetics

The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production

Proceedings of the National Academy of Sciences of the United States of America

The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing

Cell Death Differ

Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway

Proceedings of the National Academy of Sciences of the United States of America

Mutations in NALP12 cause hereditary periodic fever syndromes

Proceedings of the National Academy of Sciences of the United States of America

Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group

Nature Genetics

Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome

Nature Genetics

Isoprenoid biosynthesis in hereditary periodic fever syndromes and inflammation

Cellular and Molecular Life Sciences

A role for geranylgeranylation in interleukin-1beta secretion

Arthritis and Rheumatism

Regulatory adaptation of isoprenoid biosynthesis and the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency

Pediatric Research

CARD15 mutations in Blau syndrome

Nature Genetics

High-affinity interactions of tumor necrosis factor receptor-associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization

Biochemistry

Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes

American Journal of Physiology. Regulatory, Integrative and Comparative Physiology

The tumour necrosis factor receptor-associated periodic syndrome: current concepts

Expert Reviews in Molecular Medicine

Behcet's disease as an autoinflammatory disorder

Current Drug Targets. Inflammation and Allergy

Behcet's disease: an update on the pathogenesis

Clinical and Experimental Rheumatology

Familial Behcet's syndrome

Cutis

Significant associations of HLA-B*5101 and B*5108, and lack of association of class II alleles with Behcet's disease in Italian patients

Tissue Antigens

Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behcet disease

Proceedings of the National Academy of Sciences of the United States of America

Identification of an autosomal recessive mode of inheritance in paediatric Behcet's families by segregation analysis

American Journal of Medical Genetics. Part A

3
Autoinflammatory diseases

Significant associations of HLA-B5101 and B5108, and lack of association of class II alleles with Behcet's disease in Italian patients