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Auto inflammatory diseases (AIDs) are a group of
rare disorders characterized by persistent or recurrent inflammation caused by
the hyper activation of mediators and innate immune cells (neutrophils,
monocytes/macrophages). The paper describes the author reviews a series of
cases of the similar disease, which are given in the literature.
Keywords:
Auto inflammation, NLRP12, Inflammasome
INTRODUCTION
Auto
inflammatory diseases (AIDs) - a group of rare diseases characterized by
persistent or recurrent inflammation, caused by the hyper activation of
mediators and cells of congenital immunity (neutrophils,
monocytes/macrophages). In contrast to autoimmune diseases in AVS, the
involvement of T and B lymphocytes is only possible again, so there is no
formation of autoantibodies and a connection with antigens of the main
histocompatibility complex of HLA class II [1,2].
Innate
immunity plays a crucial role in nonspecific protection of the body against
infections using the system of recognizable receptors (pattern recognition
receptors, PRRs). These receptors recognize the molecular sequences of
pathogens and activate the immune response [3].
Interleukin
1 (IL1) is a key pro-inflammatory cytokine synthesized by monocytes, tissue
macrophages and dendritic cells. Its formation is stimulated by the influence
of microbial wall peptides, cytokines such as tumor necrosis factor (TNF),
IL18, IL1 and IL1 itself [4]. Auto induction of IL1 synthesis is the main
pathogenetic link of auto inflammation. IL1 is synthesized in an inactive form
in the form of a precursor molecule of interleukin 1 (pro-IL1), which is
activated by the enzyme caspase 1 (convertase IL1). Uncontrolled activation of
the enzyme caspase 1 in patients with a mutation in the NLRP3 gene leads to the
formation of a large amount of active IL1, which stimulates its own excess
production.
This
mechanism underlies cryopirin-associated periodic syndromes (CAPS),
characterized by sterile multi-organ inflammation [5]. In AIDS, in contrast to autoimmune diseases, the use of IL1
blockers is effective, while blocking other cytokines does not produce a result
[6].
CAPS is a
group of hereditary diseases, represented by phenotypes, differing from each
other in clinical manifestations and severity [7]. There are three forms of
CAPS: Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome
(MWS) and the neonatal Onset Multisystem Inflammatory Disease (NOMID), also
known as chronic Infantile skin neurological and articular syndrome (Chronic
Infantile Neurological Cutaneous Articular Syndrome, CINCA) [8]. All three
diseases are associated with the presence of activating mutations in the gene
NLRP3 (CIAS1), which encodes the cryopirin protein (a key component of the
inflammosome activatingcaspase 1) and determines the production rate of IL1
[9-11].
All three
forms of the disease are characterized by episodes of fever, accompanied by the
appearance of urticaroid-like rash, joint pain and an increase in acute phase
parameters. The easiest form is a family cold urticaria. This syndrome is
characterized by episodes of fever, urtikaropodobnyh rashes against the
background of joint pain and general malaise. Interestingly, for the
development of an attack, adult patients with FCAS simply have, for example, in
the department with cooling products in the store. As a rule, the disease
worsens the quality of life, but does not significantly affect its duration and
the development of irreversible organ changes.
In patients with MWS, in addition to the described
manifestations, there are hearing impairments (sensorineural hearing
loss), vision (uveitis, conjunctivitis), risk of amyloidosis (up
to 25%), delay in physical and sexual development, and a decrease in life
expectancy. Unlike FCAS, episodes of fever increase are often spontaneous and
do not have a strict connection with hypothermia, acute phase parameters
remain, as a rule, elevated even on days when fever and exanthema are absent
[12].
CINCA/NOMID syndrome is the most severe form of
CAPS, it manifests itself practically from the moment of birth, or in infancy,
and is accompanied by multiple organ damage, high risk of amyloidosis,
significant lag in physical and sexual development, influence on quality of
life and a significant reduction in its duration [13-15]. In the clinical
picture of the disease, fever, urtikaropodobnye rashes, an increased level of
acute phase parameters of inflammation are constantly present. Patients with
CINCA/NOMID syndrome have typical dysmorphic face changes, bone lesions in the
form of local tumor-like hypertrophy [16,17]. Among organ manifestations,
chronic meningitis should be noted, accompanied by signs of increased
intracranial pressure (headache, morning vomiting, skull change, ventriculomegaly),
as well as intellectual disorders of varying severity associated with brain
tissue atrophy [14,17]. Also significant are hearing impairment (sensoneural
hearing loss), vision (uveitis, conjunctivitis, papilloids), up to severe
vision loss, if the disease is not diagnosed on time and the child does not
receive adequate therapy [14].
CAPS has an autosomal dominant type of
inheritance, respectively, similar symptoms or some of them may be present in
the relatives of the patient. In most cases, in patients with typical CAMD
Symptoms, mutations are localized in the 3 exon of the NLRP3 gene, responsible
for the synthesis of the protein fragment necessary for the oligomerization
process [18]. Approximately 16% of children with CAPD mutations are sporadic
(de novo) and about 60% do not show any classical mutations. In patients with
non-classical CAPS (for example, without exanthema) mutations can be localized
in the 4 or 6 exon of the NLRP3 gene [19,20]. Up to 60% of patients with
classical CASP phenotypes do not have mutations that can be identified by
Sanger sequencing [21]. At present, this phenomenon can be explained by the
presence of somatic mosaicism, when not all cells of the body have a mutation
[22] or a genomic copy, when mutations in different genes can be manifested in
a similar clinical picture.
Interest in the NLRP12 gene as a causative factor
of fever arose due to the fact that individuals with undoubted syndrome FCAS
did not show mutations in the NLRP3 gene. In 2008 I. Jeru et al. [23] reported
three cases of NLRP12-associated disease in children. Two twin brothers who
fell ill in the first month of life had episodes of fever, hearing loss,
arthralgia and myalgia, while the level of CRP remained normal. They detected a
mutation of p.Arg284X in exon 3 of the NLRP12 gene in the heterozygous state.
In another case, in a 9 year old girl, fever arose at the age of 1 year,
accompanied by abdominal pain, vomiting, lymphadenopathy and aphthous
stomatitis, an increase in the level of CRP during the attack. The patient had
a heterozygous mutation c.2072 + 3insT in the NLRP12 gene. Several members of
the same family, especially those sensitive to cold, found the missense
mutation p.D294E in the NLRP12 gene. In the carriers of this mutation, on
contact with the cold, myalgia and arthralgia developed, whereas fever and
exanthema were absent [24]. A mutation of p.Trp408X in the NLRP12 gene
wasdetected in a family of 18 people who suffered very short attacks of fever
and urticaroid-like rash of no more than 12-24 h [25]. Symptoms were stopped on
their own, without the use of medication. In connection with the similarity of
the clinical picture in patients with a mutation in the gene NLRP12 with that in
patient with familial cold urticaria it is suggested to call this disease a
family cold type II urticaria.
In most cases, NSAIDs and short courses of
glucocorticoid therapy are effective in patients with NLPR12-associated
syndrome. In the literature, I met a description of one case where a child with
a family cold urticaria who did not have a mutation in the NLRP3 gene received
an anakin therapy to stop seizures during the cold season. In another patient,
the disease was accompanied by a delay in physical development, which was
eliminated against the background of the use of the blocker IL1 kanakinumab,
which indicates a significant effect of systemic inflammation on the child's
body.
CONCLUSION
In some cases, NLRP12-periodic syndrome in the
clinical picture resembles a family cold urticaria, in the presence of certain
mutations - MWS. In other cases, it has the features of an undifferentiated
autoimmune syndrome. The search for mutations in the NLRP12 gene should be
performed in patients with a clinical picture of familial cold urticaria and
MWS syndrome that do not have mutations in the NLRP3 gene, as well as in all
other cases of non-classical AIDS flow.
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