Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis

Abstract

Objective. Macrophage activation syndrome (MAS) in systemic onset juvenile idiopathic arthritis (SoJIA) is considered to be an acquired form of familial haemophagocytic lymphohistiocytosis (fHLH). FHLH is an autosomal recessive disorder, characterized by diminished NK cell function and caused by mutations in the perforin gene (PRF1) in 20-50% of patients. Interestingly, SoJIA patients display decreased levels of perforin in NK cells and diminished NK cell function as well. Here, we analysed PRF1 and its putative promoter in SoJIA patients with or without a history of MAS.Methods. DNA of 56 SoJIA patients (41 Italian and 15 Dutch) was isolated. Of these, 15 (27%) had a confirmed history of MAS. We sequenced PRF1 and 1.5 kb of the 5 0 -upstream region. DNA sequence variations in the promoter region were functionally tested in transfection experiments using a human NK cell line.Results. We detected a previously undescribed sequence variation (À499 C > T) in the promoter of PRF1 in 18% of the SoJIA patients. However, transfection experiments did not show functional implications of this variation. Secondly, we found that 11 of 56 (20%) SoJIA patients were heterozygous for missense mutations in PRF1. In particular, we found a high prevalence of the Ala91Val mutation, a variant known to result in defective function of perforin. Interestingly, the prevalence of Ala91Val in SoJIA patients with a history of MAS (20%) was increased compared with SoJIA patients without MAS (9.8%). One SoJIA patient, heterozygous for Ala91Val, showed profound decreased perforin levels at the time of MAS.Conclusions. These findings suggest that PRF1 mutations play a role in the development of MAS in SoJIA patients.

Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH

“…In older children and adults, a broader spectrum of clinical phenotypes (eg, encephalitis, autoimmune lymphoproliferative disease, acute lymphoblastic leukemia, aplastic anemia, and systemic onset juvenile idiopathic arthritis) 11,14,15,[30][31][32][33][34][35] have been reported. In some of these reported cases, patients were cleared from infections before the overt diseases, and therefore a negative clinical history of HLH does not rule out this syndrome.…”

Use of Rituximab in Conjunction With Immunosuppressive Chemotherapy as a Novel Therapy for Epstein Barr Virus-associated Hemophagocytic Lymphohistiocytosis

“…В основе их лежит концепция, базирующаяся на дефекте механизмов Т-клеточной цитотоксичности и снижения уровня естественных киллеров (NK) [4,22], связанных преимущественно с мутацией в гене, кодирую-щем перфорин, -PRF1 [23]. Перфорин реализует цитото-ксическое действие лимфоцита при врожденном и адап-тивном иммунном ответе, NK-клетки выделяют перфо-рин целенаправленно, что позволяет организму быстро уничтожить клетки, зараженные вирусом, и опухолевые клетки [24]. Следует отметить, что большинство пациен-тов с низким уровнем экспрессии перфорина имеют в анамнезе несколько эпизодов САМ.…”

Effectiveness of First‐Line Treatment With Recombinant Interleukin‐1 Receptor Antagonist in Steroid‐Naive Patients With New‐Onset Systemic Juvenile Idiopathic Arthritis: Results of a Prospective Cohort Study

“…However, IL-1 levels are not clearly increased in the plasma of patients with new-onset systemic JIA, whereas patients with active disease do display elevated plasma levels of IL-6 and especially IL-18, as well as elevated levels of S100 proteins (especially S100A8, S100A9, and S100A12) (13)(14)(15)(16)(17). Moreover, patients with systemic-onset JIA show deficits in the number and function of natural killer (NK) cells (6,(18)(19)(20)(21), rendering these patients susceptible to the life-threatening complication of macrophage activation syndrome (MAS) (19,20,(22)(23)(24)(25).…”