The hyper-IgD syndrome (HIDS) is a hereditary autoinflammatory syndrome characterized by recurrent episodes of fever, arthralgia, and other inflammatory symptoms accompanied by increased inflammatory markers, which are caused by mutations in the mevalonate kinase gene. Indeed, the name HIDS was derived from the fact that increased serum IgD levels were found in patients with this syndrome. Hence, the currently accurate name for the HIDS is mevalonate kinase deficiency (MKD), while the precise molecular mechanisms behind the elevated serum IgD levels and inflammation that occurs in MKD remain unknown. However, based on in-depth studies of IgD, advanced evidence suggested that a high IgD level might also play a role in the HIDS mechanism rather than a common inflammatory marker. As an advanced biotech company, Creative Biolabs established mature therapeutic antibody development platforms and we are glad to share our experience about IgD and HIDS with clients all over the world.
Fig.1 Products of the mevalonate pathway. (van der Burgh, 2013)
Clinical Presentation of Hyper-IgD Syndrome
As a rare autosomal recessive autoinflammatory metabolic disease that is caused by mutations in the MVK gene, the clinical phenotype of HIDS ranges widely, depending on the severity of the enzyme defect. Recurrent fevers, high acute-phase proteins, and elevation of serum IgD are the typical symptoms in mild phenotype while mevalonic aciduria is the most severe phenotype which leads to high mortality in infancy.
Pathogenesis of Hyper-IgD Syndrome
Mevalonate kinase (MK) is a key enzyme of the mevalonate pathway, a biosynthetic route that produces cholesterol and branched unsaturated lipid chains called non-sterol isoprenoids. However, in HIDS-affected individuals, both MVK alleles carry mutations that cause an accumulation of the mevalonate. Therefore, once activation of monocytes or macrophages leads to proinflammatory gene expression and priming of the inflammasome, increased RhoA activity promotes the expression of pro-IL-1β gene expression. As a result, inflammatory cytokines such as IL-1β are released, which contribute to pyroptosis, proinflammatory cell death, and apoptosis in bystander cells. Moreover, isoprenoid depletion also impairs the mitochondrial function of autophagic clearance of mitochondria, which further promotes IL-1β hypersecretion.
Fig.2 Pathogenesis of mevalonate kinase deficiency. (Favier, 2016)
Treatment of Hyper-IgD Syndrome
Treatment of MKD is challenging just like most autoinflammatory disorders. With the lack of radical therapeutic means, treatments should be tailored to individuals and address symptom and inflammatory control. Nonsteroidal anti-inflammatory drugs were used supportively to control inflammatory flares, while IL-1 targeting biologics including anakinra and canakinumab are gradually applied in serious HIDS especially to mevalonic aciduria. If initial biologic therapy is ineffective, a switch to a different agent or class should be considered. Finally, in patients with unremitting disease and poor quality of life, stem cell transplantation should be considered.
Fig.3 Treatment algorithm for mevalonate kinase deficiency. (Favier, 2016)
Although the mechanism of HIDS is clear, novel methods of diagnosis and treatment still remain required. Moreover, the unclear relationship between HIDS and abnormally high serum IgD levels may guide a new approach to treatment. If you are interested in the research of HIDS, or want more details in the research of the therapeutic molecular field, please feel free to contact us.
References
- van der Burgh, R.; et al. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clinical immunology. 2013, 147(3), 197-206.
- Favier, L. A.; et al. Mevalonate kinase deficiency: current perspectives. The application of clinical genetics. 2016, 9, 101-110.
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