Key words
fever - autoinflammatory - immunodeficiency - PLCG2 - IgA nephropathy
Schlüsselwörter
Fieber - Immunschwäche - PLCG2 - IgA-Nephropathie - autoinflammatorisch
Background
Autoinflammatory diseases are inherited immunological disorders caused by aberrant
activation of innate immune cells, primarily neutrophils, and macrophages. Pathogenic
inflammation of autoinflammatory diseases is attributed to the abnormal activation
of the non-antigen-dependent immune system. Several diseases manifested as recurrent
fever, and are known as periodic fever syndromes; these might also be dominated by
other clinical features.
Autoinflammatory syndromes include monogenic and polygenic diseases that manifest
as lifelong recurrent systemic inflammation with organ-specific involvement, usually
affecting the serosa, skin, joints, bones, gastrointestinal tract, and the central
nervous system. The most well-characterized autoinflammatory diseases known to be
caused by a single gene mutation.
Case report
A 26-year-old Chinese woman was diagnosed with IgA nephropathy by renal biopsy 11
years ago due to edema and hematuria, but no obvious relief from proteinuria was experienced
with glucocorticoid. After 1 year, renal biopsy was repeated in another hospital,
which also suggested IgA nephropathy with focal crescent formation. After glucocorticoid
and cyclophosphamide pulse treatment, proteinuria was relieved gradually. Fever was
detected repeatedly from November 2012 to February 2018, and each time, it lasted
for several days. The normal features included procalcitonin, blood culture, erythrocyte
sedimentation rate, C-reactive protein, disruption of liver and kidney function, electrolytes,
fungal examination, anti-neutrophil cytoplasmic antibody, autoantibodies lupus antibodies,
tumor markers, serum protein electrophoresis, immunity fixed electrophoresis, endocrine
hormones, and no abnormalities in the head, chest, and abdomen CT. In addition, there
were no positive findings such as bone marrow puncture and lumbar puncture as assessed
by bone marrow flow cytology. No significant relief was experienced by antibiotics,
glucocorticoid, immunosuppression, and diagnostic anti-tuberculosis treatment, and
five years ago, the skin of the forearm was found to be red and itchy. From 2016 to
2017, the patient stopped using glucocorticoids and immunosuppressants after remission,
had a successful pregnancy, and gave birth to a healthy boy at term. During pregnancy,
the patientʼs fever disappeared spontaneously, and no drugs, including antipyretics,
were applied.
In June 2018, the fever recurred, and after the activity, gasping, intermittent hemoptysis,
abdominal pain, chest pain, hematuria, intermittent hypertension/hypotension (180/110 mmHg,
80/50 mmHg, respectively), and often fall, electrocardiogram showed frequent ventricular
premature beats. However, the T cell subsets were normal , IL-6: 4.15 pg/mL(reference:
0.1–2.9) , and virus test negative. Chest CT indicated pulmonary interstitial changes
and pulmonary granuloma. No obvious positive findings were observed by gastroscopy,
Congo red staining was negative in the gastric mucosa, and no positive findings were
detected in bronchoscopy, and Congo red staining of 10-year-old renal tissue samples
showed negative results. Previously, the patient had knee pain in early childhood
and intermittent headache for 12 years. One year ago, the MR of the knee showed an
abnormal signal of the right femur and tibia, considering metabolic changes, softening
of the tibial cartilage, and a small amount of effusion in the supraorbital sac and
joint cavity. No relief was experienced with glucocorticoids and antibiotics. In July
2018, the whole exon gene test revealed a mutation in the PLCG2 gene, chr16:81902844, c.505A>G.p.lle169Val ([Fig. 1]), while back skin biopsy suggested amyloidosis ([Fig. 2]. HE staining suggests amyloid deposition in the subcutaneous papilla, 4×10-fold).
The patientʼs father was heterozygous, and the mother had no abnormalities at that
site. The family had no history of similar diseases.
Fig. 1 The whole exon gene test revealed a mutation in the PLCG2 gene, chr16:81902844, c.505A>G.p.lle169Val.
Fig. 2 Back skin biopsy suggested amyloid deposition in the subcutaneous papilla (HE staining
4×10-fold).
According to the patientʼs medical history, the final diagnosis was autoinflammatory
PLCG2-associated antibody deficiency and immune dysregulation (APLAID). Hence, rilonacept
(160 mg qd) was administered for 2 weeks; the fever was relieved gradually, and no
adverse and unanticipated events were observed at the follow-up.
Discussion
Genetically defined, autosomal dominant human primary immunodeficiencies have been
found to manifest in various combinations of phenotypes belonging to five broad categories:
autoimmunity, autoinflammation, allergy, infection, and malignancy [1]. PLCG2-related immunodeficiencies are associated with the first four, and there is no evidence
of an association with malignancies [2].
APLAID is an autoinflammatory disease, with PLCG2 gene mutation as the characteristic Change [1]. PLCG2 encodes phospholipase Cγ2 (PLC gamma 2), an enzyme with key regulatory roles in various
immune and inflammatory pathways [1]. Recent evidence suggested that PLCG2 mutations are involved in several human pathologies. Deletions of exons 19 or 20–22
cause cold urticaria and PLCγ2-associated antibody deficiency and immune dysregulation
(PLAID) [3]
[4], while a point mutation (S707Y) is the basis of autoinflammation and PLCγ 2-associated
antibody deficiency as well as immune dysregulation (APLAID) [3].
Interestingly, the patient did not use any medication during pregnancy, the disease
ceased to appear, no fever and other related discomforts were noted, and a baby boy
was was born successfully. Reportedly, familial Mediterranean fever and Periodic fever
aphthous-stomatitis pharyngitis cervical-adenitis syndrome (PFAPA) patients may experience
remission after pregnancy, which could be attributed to changes in hormones during
pregnancy [5]. It is speculated that PFAPA syndrome is a Th1-type immune disease that may be improved
by Th1 to Th2 shift caused by pregnancy [6]. Presently, there is no report of APLAID combined with pregnancy, and the correlation
between self-inflammation and pregnancy should be investigated.
Some patients with periodic fever can be combined with amyloidosis, Muckle-Wells syndrome
(MWS), and familial Mediterranean fever patients can be complicated by amyloidosis,
proteinuria, and renal failure [7]
[8]; however, APLAID/PLAID complicated with amyloidosis has not been reported. In this
case, patients with gastrointestinal bleeding and intermittent chest pain showed arrhythmia
on the electrocardiogram, while blood pressure fluctuations considered disruptions
in the digestive tract, myocardium, and amyloidosis of the heart conduction system
.
APLAID combined with IgA nephropathy has not yet been reported. Previous studies have
shown that IL-1 β is involved in the pathogenesis of spontaneous and passively induced
IgA nephropathy models, in which the activation of NLRP3 inflammasome contributes
to the pathogenesis of IgA nephropathy [9]. In addition, Robinet et al. reported a case of Muckle-Wells syndrome with IgA nephropathy
and renal amyloidosis, both fever and proteinuria were significantly reduced by using
interleukin-1 blocker [10]. We hypothesized that over-activation of IL-1 may be involved in the pathogenesis
of both APLAID and IgA nephropathy.
Autoinflammatory diseases manifest multiple features of the central nervous system,
including chronic aseptic meningitis and brain atrophy, sensorineural hearing loss,
early-onset hemorrhagic and ischemic strokes, mental retardation, cerebellitis, ataxia,
and severe encephalopathy with brain calcifications [11]. However, APLAID combined with central nervous system performance has not yet been
reported. In this case, the patient had repeated ataxia, headache, nausea, and vomiting,
but no obvious abnormalities in the head MR. Thus, the specific mechanism is still
unclear.
Most autoinflammatory diseases are associated with the overproduction of IL-1 and
IL-6 [10]. With the introduction of anti-IL-1 drugs, the treatment of such diseases has become
effective. Currently, three commercially available anti-IL-1 drugs are anakinin, rilonacept,
and canakinumab [13]. Some patients with cryopyrin- associated periodic syndromes
(CAPS), such as IL-1 blockers, are ineffective, and IL-6 blockers can also be tested
[13]. Reportedly, IL-1 blockers have achieved significant effects in the treatment
of ocular lesions in patients with PLAID [12]. This patient also experienced symptoms relief after intramuscular injection of
rilonacept 160 mg weekly.
APLAID complicated with gastrointestinal bleeding and ataxia has not been reported
before, and the specific pathophysiological mechanism is currently unclear. Thus,
and further laboratory studies are essential with additional cases. Also, no other
accompanying symptoms were noted in the early stage of fever. As the disease progressed
and repeated, respiratory, digestive, cardiovascular, and other systemic damages appeared
eventually, suggesting that APLAID may be poor in the absence of effective treatment.
In summary, APLAID appears in a variety of phenotypes and damage to multiple systems,
such as skin, gastrointestinal tract, lungs, cardiovascular, bones, central nervous
system, endocrine and immune system, and accompanied with amyloidosis. The specific
pathophysiological mechanism of APLAID was complicated with multiple system damage,
and hence, the correlation between autoinflammatory diseases and IgA nephropathy as
well as pregnancy needs further investigation.
Authorsʼ contributions
ZFJ was responsible for the diagnosis, treatment, follow-up, writing, and submission
of the report. AQF was involved in the diagnosis and treatment of the patient. TL
was involved in the diagnosis and treatment of the patients.
Consent for publication
The figure and clinical information in this article were utilized for verbal consent
from the patient.
