Hyperimmunoglobulin D syndrome: Pathophysiology

INTRODUCTION — Hyperimmunoglobulin D syndrome (HIDS) is a rare genetic disorder characterized by recurrent febrile episodes typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D (IgD) level (MIM #260920). The syndrome can be further categorized into classic and variant forms. The genetic defect is known in the classic form, which makes up 75 percent of cases. The variant form has similar clinical manifestations, although its genetic basis is unknown [1].

This topic reviews the genetics and pathophysiology of HIDS. The clinical manifestations, diagnosis, and management of this disorder are discussed in detail separately. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "Hyperimmunoglobulin D syndrome: Management".)

GENETICS — Classic HIDS is caused by mevalonate kinase (MVK) deficiency and is inherited as an autosomal-recessive trait [2-6]. Most patients are compound heterozygous for two different mutations in the MVK gene [7-9]. However, some patients may be homozygous for the same defect on both alleles [10]. Patients with similar clinical features but lacking mutant MVK genes are referred to as having variant HIDS. (See 'Variant HIDS' below.)

Mevalonate kinase — The MVK gene (MIM *251170) is located on the long arm of chromosome 12 (12q24) [11]. The gene product, MVK, is a cytosolic protein that is localized to the peroxisome [12,13]. It is an enzyme in the cholesterol synthesis pathway. This pathway is responsible for the synthesis of sterol products, such as cholesterol and its derivatives, as well as nonsterol isoprenoids, including prenylated proteins, heme A, dolichol, and ubiquinone 10 [14,15]. MVK is one enzyme downstream of the highly regulated hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase enzyme (figure 1).

Compound heterozygous MVK mutations in HIDS patients usually consist of one allele with a mutation that causes mevalonic aciduria when present in a homozygous state (eg, H20P, I268T, or A334T mutation) [16] (see "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Mevalonic aciduria'). The other allele has a mutation that is not typical for mevalonic aciduria. The V377I mutation is the most common mutation in patients with HIDS (52 to >90 percent) [11,17-19]. In the remaining HIDS patients without the V377I mutation, the second mutation probably causes a similar enzymatic defect, leading to residual MVK activity [2].

The V377I mutation and others like it probably prevent appropriate folding of newly formed MVK proteins at body temperature (37°C), thereby causing decreased in vivo enzyme activity [14,19]. A mouse model of HIDS was created via the deletion of a single MVK allele, supporting diminished MVK activity as the probable cause of HIDS [20].

Other genetic factors — The estimated incidence of HIDS is 1:5000 to 1:50,000 in the general population, although the observed incidence is much lower, suggesting decreased penetrance of the disease [16,21]. Autosomal-recessive homozygous genotypes, especially of the V377I mutation, are encountered with less frequency than expected, assuming these mutations are in Hardy-Weinberg equilibrium within the population, suggesting incomplete penetrance of this genotype specifically [4,16].

Homozygous V377I mutations would theoretically allow for double the enzymatic activity found in compound heterozygous HIDS patients with a V377I and a nonfunctional allele (eg, H20P, I268T, or A334T mutations), with a range of 1 to 12 percent of residual enzyme activity expected. This configuration may or may not result in sufficient reduction of enzymatic activity to yield the HIDS phenotype, thereby contributing to the observed incomplete penetrance [16]. As an example, of two sisters with identical homozygous V377I mutations, only one was symptomatic [22]. In addition, other minor mutations may be present in downstream enzymes in such homozygous patients who demonstrate the HIDS phenotype [23].

Variant HIDS — Defects in downstream enzymes have been proposed to account for variant HIDS, given that the phenotypes are essentially the same [24]. Such mutations would also create a lack of nonsterol isoprenoids, one of the mechanisms proposed to cause febrile episodes in classic HIDS. It is likely that these conditions will take on other names as the gene mutations underlying variant HIDS are identified. It is also possible that regulatory region mutations for MVK itself exist that evaded identification via standard sequencing of the gene. (See 'Nonsterol synthesis pathway products' below and "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Variant HIDS'.)

Overlap syndromes — Mutations found in other rare periodic fever syndromes have been identified in some HIDS patients [25,26]. These "overlap syndromes" may account for clinical features that are unusual in HIDS patients, such as amyloidosis [27-29]. One patient with HIDS and systemic amyloidosis was homozygous for the alpha/alpha genotype of the serum amyloid A 1 (SAA1) gene and was also a compound heterozygote for HIDS mutations (H20P and V250I) [29]. Such coincidental mutations may also account for atypical responses to medical treatment [30]. Further genetic and clinical studies on patients with hereditary periodic fever syndromes are required to support the concept of overlap syndromes. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis", section on 'Overlap syndromes'.)

PATHOPHYSIOLOGY — A successful explanatory model of HIDS pathophysiology needs to account for the periodicity of fevers, the frequent presence of increased serum levels of immunoglobulin D (IgD) and/or immunoglobulin A (IgA), and the HIDS phenotype in patients with no identifiable mutations in the MVK gene. Although reduced MVK enzyme activity that results from mutations in the MVK gene is responsible for many cases of HIDS, the definitive pathophysiologic mechanisms through which the genetic defect causes the HIDS phenotype remain unknown.

One explanatory model begins with triggering events that cause transient elevations in body temperature. Temperature sensitivity of the MVK enzyme leads to the decreased production of mevalonate 5-phosphate and downstream nonsterol isoprenoids, particularly those with high turnover (ubiquinone 10 in patients with mevalonic aciduria and antiinflammatory isoprenoids in HIDS patients), promoting a proinflammatory phenotype with more fever and inflammation [14,19]. In HIDS patients, this cascade leads to increased 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity that increases mevalonate levels and drives production of nonsterol end-products despite persistently decreased MVK enzyme activity at higher temperatures. Eventually, homeostasis is restored, and the febrile episode ends. This theory explains why events such as vaccinations, minor trauma, surgery, or stress can trigger an attack in HIDS patients and is in general agreement with the observed phenotype and the above in vitro data. More clinical and molecular studies are required, though, before this theory can become widely accepted.

Serum immunoglobulin D — Some in vitro experimental data suggest that IgD is part of the autoinflammatory process rather than an epiphenomenon. This proinflammatory effect was illustrated when peripheral blood mononuclear cells (PBMCs) from normal patients were exposed in vitro to IgD purified from an HIDS patient [31]. Large quantities of interleukin (IL) 1, IL-6, IL-1 receptor antagonist (IL-1Ra), and tumor necrosis factor alpha (TNF-alpha) were detected. IgD also enhanced cytokine production in response to lipopolysaccharide (LPS), a potent inducer of inflammatory cytokines.

The degree of O-glycosylation of IgD and IgA1 may alter the inflammatory nature of these immunoglobulins. The T cell IgD receptor is a lectin that has a binding affinity for the O-glycans of IgD and IgA1. Patients with HIDS have increased O-galactosylation of IgD and decreased O-sialylation of both IgD and IgA1 compared with normal controls [32]. This may have a significant effect on basal immunoglobulin synthesis, as well as myeloid cytokine release. However, serum IgD and its O-galactosylation are elevated between, as well as during, attacks. In addition, IgD levels do not appear to correlate with the frequency or severity of attacks [33].

Mevalonate — In patients with HIDS, increased excretion of mevalonate (mevalonic aciduria) is transient and only occurs during febrile episodes. Studies suggest that elevated mevalonate (mevalonic acid) levels more likely help to prevent attacks than to promote them [34]. As an example, treatment of two patients with the HMGR inhibitor lovastatin, which should have reduced mevalonate synthesis, resulted in severe crises in both cases [35].

Supplying metabolic products downstream of mevalonate may have a favorable antiinflammatory effect. This was illustrated in an in vitro study using PBMCs from patients with HIDS [36]. Production of IL-1 beta was increased relative to that from PBMCs of healthy controls. A further increase in IL-1 beta was noted following blockade of HMGR using lovastatin but was partially reversed by adding farnesol (FOH) and geranylgeraniol (GGOH), two downstream intermediates in the cholesterol synthetic pathway. FOH decreased IL-1 beta production by 62 percent in cells from HIDS patients. Adding mevalonic acid caused a smaller effect but also decreased, rather than increased, IL-1 beta release.

Sterol synthesis pathway products — A deficiency of cholesterol or its derivative seems unlikely to be important in causing fever or other symptoms of HIDS. Patients with HIDS appear to have normal cholesterol levels [37] and continued cholesterol synthesis in cultured cell lines [34].

Nonsterol synthesis pathway products — Disruption of cellular signaling caused by decreased production of nonsterol pathway products, cytokine derangements, and an inflammatory process seem plausible results of partial MVK enzyme deficiency. However, this does not explain the limited and periodic nature of HIDS attacks.

Molecular studies in a mouse model, cell lines, and primary human cells further support this theory [38-44]. A mouse model, where the isoprenoid pathway is inhibited by bisphosphonates and inflammation is further stimulated by bacterial muramyl dipeptide, showed an increased inflammatory response [44]. This response was attenuated by the addition of exogenous isoprenoids (geraniol, farnesol, and geranylgeraniol). RAW264.7 cell lines and primary monocytes from healthy controls demonstrated similar effects, with lipopolysaccharide replacing muramyl dipeptide as the additional stimulus [41]. In cellular and animal models, inhibition of the mevalonate pathway with a bisphosphonate (alendronate or pamidronate) increased expression of NLRP3 (nacht domain-, leucine-rich repeat-, and pyrin domain-containing 3), a key inflammasome component and mediator of innate immunity linked to IL-1 beta secretion [38,42].

The inflammation in these models was also reduced by the addition of manumycin A, an inhibitor of farnesyl transferase, which prevented the consumption of farnesyl pyrophosphate and increased the production of geranylgeranyl pyrophosphate (figure 1). Newer farnesyl transferase inhibitors, tipifarnib and lonafarnib, demonstrated similar effects [43]. It is therefore proposed that the inflammatory response is linked to a shortage of geranylgeranyl pyrophosphate, which is in agreement with other studies linking geranylgeranylation with IL-1 beta activation [45-47].

Some cholesterol biosynthetic pathway intermediates, such as polyisoprenyl phosphates (PIPP), presqualene diphosphate (PSDP), and presqualene monophosphate (PSMP) may serve as potent signaling molecules [48]. The nonsterol end-products, the isoprenoids, also play important cellular roles, including as components of prenylated proteins (cytokine signaling, cell cycling, cell development), heme A (electron transport), dolichol (glycoprotein synthesis), ubiquinone 10 (electron transport, antioxidant), and isopentenyl tRNAs [14,15]. Some small G-proteins, which are involved in cellular signaling, are prenylated proteins.

One such G-protein of the Rho family, Rac-1, plays a critical role in caspase 1 activation through inflammasome oligomerization [34,49]. The NLRP3 inflammasome is linked to familial Mediterranean fever (FMF) and cryopyrin-associated periodic syndromes (CAPS). Rac-1 has increased activity in the presence of simvastatin, an HMGR inhibitor [45,50]. Other studies have shown that inhibition of the mevalonate pathway with a geranylgeranyl-transferase inhibitor and with simvastatin leads to a caspase 1-dependent release of IL-1 beta and IL-18 by activated monocytes [45,50,51]. Farnesyl transferase inhibitors block this effect [50]. Additionally, dermal fibroblasts cultured from healthy donors increased production of IL-1 beta to levels matching that of dermal fibroblasts cultured from mevalonate kinase-deficient (MKD) donors when exposed to simvastatin. Combining simvastatin with mevalonate reduces IL-1 beta production in fibroblasts from healthy donors but not in those from MKD donors [52].

Secondary mediators — Regardless of the primary cause, cytokine activation is thought to contribute to the symptoms experienced by patients with HIDS during febrile episodes. Elevated circulating IL-6 and TNF-alpha levels are present during febrile episodes compared with asymptomatic intervals [53]. IL-6 levels correlate significantly with C-reactive protein (CRP) levels. Antiinflammatory molecules, such as IL-1Ra and soluble TNF receptor superfamily 1A (sTNFRSF1A: sTNFr p55 and p75) are also elevated during attacks. Inflammatory IL-1 alpha, IL-1 beta, and the antiinflammatory cytokine, IL-10, levels were not elevated during febrile episodes.

Persistently elevated alpha1-acid glycoprotein (AGP) in patients with HIDS compared with normal controls points to a continued inflammatory state even between attacks [54]. Finally, increased urinary neopterin levels in HIDS patients during febrile episodes, which normalize between attacks, represent products of monocytes and macrophages that have been stimulated by interferon gamma [55].

SUMMARY

●Hyperimmunoglobulin D syndrome (HIDS) is characterized by febrile episodes that are typically associated with lymphadenopathy, abdominal pain, and an elevated serum polyclonal immunoglobulin D (IgD) level. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis".)

●Mutations of the mevalonate kinase (MVK) gene are responsible for the autosomal-recessive pattern of inheritance seen in many cases of the classic HIDS. Impaired folding of the MVK protein at body temperature may play a role in decreased enzyme activity. A similar phenotype may occur in the absence of mutations of the MVK gene and is referred to as variant HIDS. (See 'Genetics' above.)

●The pathophysiology of HIDS and mevalonic aciduria are incompletely understood. Although IgD levels are typically elevated in HIDS, it is unlikely that elevated serum levels of IgD are responsible for the periodic fevers and other symptoms of HIDS. (See 'Serum immunoglobulin D' above.)

●Neither the increased production nor the increased excretion of mevalonate (mevalonic acid) appears to be the proximate cause of the inflammatory phenotype. Attempts to decrease mevalonate production using statin drugs in patients with HIDS have led to worsening of disease.

●Decreased availability of nonsterol biosynthetic pathway intermediates (which may have antiinflammatory properties) may be of pathophysiologic importance. In vitro studies suggest that supplying exogenous precursors (farnesol and geranylgeraniol) for downstream products may reduce the production of proinflammatory cytokines from cultured cells from patients with HIDS. Additionally, inhibition of farnesyl transferase may also reduce proinflammatory cytokines by increasing the availability of geranylgeranyl-PP. (See 'Nonsterol synthesis pathway products' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.