SPAID – Shar-Pei Autoinflammatory Disorder
SPAID is a term to describe the spectrum of clinical signs due to systemic and persistent inflammation in Chinese Shar-Pei. All the signs in SPAID are autoinflammatory in nature and are related elevated levels of hyaluronan, a molecule which functions as a danger signal (a DAMP) that triggers the inflammatory response. SPAID resembles human AID (autoinflammatory disease) that also presents with multiple inflammatory signs. Many Shar-Pei with SPAID also receive relief from disease by the use of IL-1β inhibitors which suggests a cytokine-driven inflammation and a dysregulation of the innate immune response. SPAID definitely is linked to increased levels of LMW-HA (low molecular weight hyaluronan) which appears to be a breed characteristic related to strong selective breeding for the heavily wrinkled phenotype.
Involves a genetic defect in the innate immune system caused by a mutation in a regulatory gene upstream of the HA2S gene on chromosome 13. The mutation occurs in two forms: the so-called “traditional” and “meatmouth” mutation. The mutation is a duplication resulting in a Copy Number Variation (CNV). This mutation is responsible for the increase in hyaluronan levels seen in this breed. The mutation appears to involve a regulatory gene for the Hyaluronan Synthase 2 gene (HAS2) which produces hyaluronan (HA). It appears HAS2 over-expression is driving the amplified production of hyaluronan and in turn, driving the canine AID state. The amount of HA is responsible for the variation in the “wrinkling” phenotype which is unique to the Shar-Pei. A higher copy number is also significantly associated with the risk of experiencing recurrent fever attacks as well as chronic recurrent otitis, hock swelling/arthritis, vesicular hyaluronosis (HCH), inflammatory bowel disease and amyloidosis). This seems to hold true only for the “meatmouth duplication and doesn’t occur with the “traditional duplication”.
LMW-HA induces inflammation through two mechanisms:
- Binding to TLR2 or TLR4 which activates NFƙβ which leads to an increase in IL-1β
- Binding to CD44 which is recognized by NLRP3 and activates the inflammasome leading to the transformation of pro-IL-1β into IL-1β. IL-1β is the principal cytokine in SPAID.
- LMW-HA is recognized as a DAMP (danger-associated molecular pattern)
The autoinflammatory is now called SPAID and manifests as a number of clinical signs such as:
- Familial Shar-Pei Fever (FSF)
- Amyloidosis—due to a potential modifier locus on chromosome 14.
- Recurrent otitis
- Hereditary Cutaneous Hyaluranosis (HCH) – formerly “cutaneous mucinosis”
27 Mb duplication determines breed type and dermatitis
23.5 Mb duplication determines fever, arthritis and amyloidosis
The gene duplication region is located 350 Kb upstream from HAS2.
Bottom line: Increased LMW-HA is a major risk factor for SPAID
Other associations with SPAID?
Predisposition to aggressive mast cell disease
Streptococcal Toxic Shock Syndrome/Necrotizing Fasciitis
Lymphangitis, lymphedema, Lymphangectasia
Swollen Hock Syndrome (SHS) with or without pyrexia
Inflammatory Bowel Disease (IBD)
HA has a dual role in the inflammatory response. Low MW HA can serve as a danger associated molecular pattern (DAMP) and activate the inflammasome and the release of pro-inflammatory interleukins (pro-ILs) by two routes. In one route HA acts on toll-like receptors (TLR2 and TLR4), activating NF-ƙβ to produce immature pro-ILs. In the second pathway HA binds to the cellular receptor CD-44, followed by hyaluronidase cleavage by HYAL2 at the membrane and HYAL1 in the lysosome. This produces the small oligosaccharides of HA which actually trigger inflammasome complex formation. BOTH routes must be for active cytokines to be released from the cell.
The distinguishing feature of many of the AIDs is the dysregulated secretion of the inflammatory cytokine interleukin -1β (IL-1β). HAS2 serves as a rheostat during inflammation. The pathological outcomes and clinical signs of autoinflammatory disease (AID) result from a dysregulation of the innate immune response. In Shar-Pei it appears that HAS2 over-expression is driving the amplified production of hyaluronan and, in turn, drives the canine AID state.
There is clear localization of the genetic signal for breed subtype with the peaks of association for each of the SPAID phenotypes. There were two signals on chromosome 13, one at ~22-23 Mb and the other between~27-29 Mb. Genetic duplications in this region, which is upstream from HAS2, result in overproduction of HA which affects the phenotype and predisposition to AID.
Within the larger genomic region in breed subtype differentiation there are two genes involved in collagen production and recognition as well as genes essential for the immune response and kidney function. These could account for the various disease presentations included in FSF.
There was also noted a signal of association to amyloidosis on chromosome 14. Continuous, cyclic production of HA can lead to chronic states of inflammation and result in an acute phase response with up to a 1000-fold increase of hepatic serum amyloid A (SAA) production. SAA is a key modulator of the innate immune response and can provide the two signals required for the inflammasome-mediated release of interleukins. SAA activates the NF-ƙβ pathway through direct binding with TLR4 similar to HA. However, its activation of the inflammasome is via binding to the cellular receptor P2X.
HA and SAA are acting as Danger Associated Molecular Patterns (DAMPs) to trigger formation of the inflammasome. An individual’s genetic predisposition to DAMP/PAMP stress response may directly impact their susceptibility to amyloidosis.
1. Olsson M, Tintle L, Kierczak M, et al.(2013 “Thorough Investigation of a Canine Autoinflammatory Disease (AID) Confirms One Main Risk Locus and Suggest a Modifier Locus for Amyloidosis”, PLoS Genet. 8(10):e75242.
2. Olsson M, Meadows JR, Truvè, Rosengren Pielberg G, Puppo F, et al.(2011), “A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs”. PLoS Genet. 7(3):e1001332.
Jeff Vidt, DVM