Which are the causes of Hyper-IgD Syndrome / Hyperimmunoglobulinemia D With Recurrent Fever (HIDS)?

Hyper-IgD Syndrome, also known as Hyperimmunoglobulinemia D with Recurrent Fever (HIDS), is a rare autosomal recessive genetic disorder that primarily affects the immune system. It is characterized by recurrent episodes of fever accompanied by various symptoms such as abdominal pain, joint pain, headache, and skin rashes. The exact cause of HIDS is still not fully understood, but several factors have been identified as potential contributors to the development of this condition.

Genetic Mutations: HIDS is caused by mutations in the mevalonate kinase (MVK) gene, which is responsible for producing an enzyme involved in the biosynthesis of cholesterol and other essential molecules. These mutations lead to a deficiency of mevalonate kinase, resulting in the accumulation of certain metabolites and the dysregulation of the immune system.

Autoinflammatory Response: The immune system of individuals with HIDS is hyperactive, leading to an exaggerated inflammatory response. This abnormal immune response is thought to be triggered by various factors, including infections, stress, vaccinations, or other environmental triggers. The exact mechanism by which these triggers induce the recurrent fever episodes is not fully understood.

Dysregulated Interleukin-1 (IL-1) Pathway: IL-1 is a pro-inflammatory cytokine that plays a crucial role in the regulation of immune responses. In HIDS, there is an imbalance in the IL-1 pathway, resulting in increased production of IL-1β, a potent inflammatory mediator. This dysregulation contributes to the recurrent fever episodes and other symptoms associated with HIDS.

Impaired Mevalonate Pathway: The mevalonate pathway, in which the MVK gene is involved, is essential for the production of cholesterol and other important molecules. The dysregulation of this pathway in HIDS affects various cellular processes, including the regulation of inflammation and immune responses. The accumulation of certain metabolites due to the impaired mevalonate pathway is believed to contribute to the symptoms of HIDS.

Genetic Predisposition: Although HIDS is a genetic disorder, not all individuals with MVK gene mutations develop the condition. There may be additional genetic or environmental factors that influence the expression and severity of the disease. Further research is needed to fully understand the genetic predisposition to HIDS.

In conclusion, Hyper-IgD Syndrome or Hyperimmunoglobulinemia D with Recurrent Fever (HIDS) is primarily caused by genetic mutations in the MVK gene, leading to a deficiency of mevalonate kinase and dysregulation of the immune system. The autoinflammatory response, dysregulated IL-1 pathway, impaired mevalonate pathway, and potential genetic predisposition all contribute to the development and symptoms of HIDS. Further research is necessary to unravel the complex mechanisms underlying this rare genetic disorder.