Autoinflammatory Disease


Since the elucidation of the human and canine genomes our understanding of the genetic mechanisms underlying the inflammatory response has progressed at an exponential rate. We now realize that genes encode for proteins that serve as enzymes in biochemical pathways, as receptors on cell membranes, as chemical messengers in the body such as cytokines/chemokines and regulatory proteins which control various processes in the body — primarily the inflammatory response and the innate and adaptive immune responses. It is even more complex as some proteins (chemokine receptors) have a role as ‘silent’ (non-signaling) receptors which regulate inflammatory and immune reactions by acting as decoys and scavengers. All this serves to keep the body in “homeostasis” or a state of physiological equilibrium. One process in the body which certainly concerns us as Shar-Pei owners is the inflammatory process, especially as it related to Familial Shar-Pei Fever. Not only is more being discovered about the inflammatory pathways themselves but also about the system of checks and balances which keep this process under tight control. Genes have been discovered which are “proinflammatory” and which are “anti-inflammatory”. Mutations in these genes are responsible for a wide range of autoinflammatory diseases in humans and we have reason to believe they do occur in animals as well. As research leads to a better understanding of the inflammatory response and its aberrations it also will give us new modalities of treatment for these conditions.

The category of autoinflammatory disease was first proposed in 1999 to describe a group of inherited disorders characterized by:

  1. Episodes of unprovoked (?) inflammation.
  2. The absence of high-titer autoantibodies or antigen specific T-cells usually seen in auto- immune diseases.
  3. Often being accompanied by periodic fevers.

Examples include a large category of diseases known as the Hereditary Recurrent Fever Syndromes or HFRs. In this category are Familial Mediterranean Fever (FMF), Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulinemia-D with Periodic Fever Syndrome (HIDS), and Cryopyrin-Associated Periodic Syndromes (CAPS) and maybe Familial Shar-Pei Fever (FSF)?

Other autoinflammatory diseases are Pyogenic Arthritis with Pyoderma Granrenosum and Acne (PAPA), Periodic Fever with Aphthous Stomatitis, Pharyngitis and Cervical Adenopathy (PFAPA), and Behçet’s disease, Idiopathic Pulmonary Fibrosis.

Mutations in MEFV Gene

  • Responsible for FMF
  • MEFV gene encodes for the pyrin/marenostrin protein. This protein contains a PYRIN domain which is also seen in the cryopyrin protein in CAPS. This domain facilitates protein-protein interactions.

TRAPS (Tumor Necrosis Factor Receptor-Associated Periodic Syndrome)

  1. This category includes Familial Hibernian Fever, benign autosomal dominant familial periodic fever and autosomal dominant periodic fever with amyloidosis.
  2. Caused by a protein mutation in the p55 TNF receptor (TNFRSF1A).
  3. Currently 40 mutations known.

CAPS (Cryopyrin-Associated Periodic Syndrome)

  1. This category includes familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID) also called chronic infantile neurologic cutaneous and articular syndrome (CINCA).
  2. Caused by a mutation in the CIAS1 (also known as cryopyrin or NALP3) protein which encodes a protein that regulates the activity of caspase-1. Currently 35 mutations known.
  3. Caspase-1 is a protein that plays an important role in inflammation. A mutation in the cryopyrin gene causes three autoinflammatory diseases: Muckle-Wells syndrome, familial cold autoinflammatory syndrome and neonatal-onset multisystem inflammatory disease.
  4. Collectively, these diseases are called cryopyrin-associated periodic syndromes (CAPS).
  5. Caspase-1 regulates the processing and secretion of three interleukin proteins: IL-1?, IL-18 and IL-33. Caspase-1 activity is critical for the inflammatory response.

The Inflammasome

  1. This is a molecular platform triggering activation of inflammatory caspases and processing of proIL-1?.
  2. The inflammasome comprises caspase-1, caspase-5, Pycard/ASC and NALP1.
  3. Pycard appears to connect the CARD (caspase recruitment domain) of caspase-1 to the PYD (CARD-like Pyrin domain) of NALP1.
  4. Caspase-1 cleaves proIL-1? generating the proinflammatory IL-1?. This process occurs most efficiently when both caspase-1 and caspase-5 are coactivated.
  5. PYRIN Domain
  6. Pyrin
  7. Cryopyrin
  8. Apoptosis-associated specklike protein with a
  9. CARD (ASC)
  10. Both pyrin and cryopyrin have been shown to harbor HRF-associated mutations. So far no disease-producing mutations have been found in ASC.

Caspase Regulation

  1. Pycard is essential for the maturation of the proinflammatory caspases.
    1. Coexpression of Pycard and caspase-1 induces caspase-1 processing.
    2. Removal of Pycard or its neutralization results in failure to activate caspase-1and caspase-5.
    3. Activation of both caspase-1 and caspase-5 is blocked by an abnormal Pycard which binds NALP1 but cannot recruit caspase-1.

The take home lesson is that it appears mutations in the NALP region (or at least the NALP3 region) may lead to a deregulated activation of proinflammatory caspases resulting in spontaneous fever episodes.

New research has demonstrated that gout- and pseudogout-associated uric acid crystals activate the NALP3 inflammasome resulting in production of active interleukin 1-? and IL-18. This provides some explanation for the usefulness of colchicine in FSF. Colchicine appears to block crystal-induced IL-1? generation upstream of inflammasome activation. It is probably useful in autoinflammatory diseases because it blocks IL-1? production caused by NALP3 mutations.

Cryopyrin, pyrin and the p55 TNF receptor play an important role in regulating cytokine secretion, nuclear factor-?B activation and apoptosis, and thereby the innate immune system.

Systemic amyloidosis is one of the most serious manifestations of the HRFs and is the result of the tissue deposition of misfolded fragments of serum amyloid A (SAA), one of the acute phase reactants produced by the liver in response to systemic inflammation.

Death Domain-Fold Superfamily Currently composed of 4 members

  1. The death domain
  2. The death effector domain
  3. The caspase-recruitment domain (CARD)
  4. The PYRIN domain

The gene mutation variant may determine the clinical course of the disease in a particular individual.

  1. One of the MEFV variants in FMF is associated with prolonged fevers, mainly joint involvement, colchicine resistance and an autosomal dominant mode of inheritance.
  2. An additional complicating factor involved in the HRFs involves modification of the SAA1 precursor which is under separate genetic control. It has been demonstrated that the ?/? genotype confers increased risk for amyloidosis.
  3. Hence, in FMF, there is an increasing body of knowledge which shows that there are MEFV- independent modifying factors for FMF.


  1. In FMF patients upregulation of neutrophil and monocyte function is seen during remission (between episodes) and downregulation during an attack.
  2. Increased endotoxin sensitivity is seen in periods of remission.
  3. Chronic inflammation during FMF is characterized by periodic changes in monocyte and neutrophil activation and a heightened sensitivity to
  4. endotoxin.
  5. Endotoxins are bacterial lipopolysaccharides associated with Gram-negative bacteria. Could a similar mechanism be associated with the exotoxin produced by Streptococcus bacteria and increase susceptibility to STSS (Streptococcal Toxic Shock Syndrome) or Necrotizing Fasciitis (NF)?
  6. Induction of homologous tolerance to endotoxin by monocytes is observed during FMF episodes.
  7. Colchicine is able to restore impaired endotoxin homologous tolerance induction via an increase in IL-4 synthesis by monocytes in the period of remission.
  8. Colchicine is able to inhibit the periodic changes in monocyte and neutrophil activation and downmodulates the increased sensitivity to endotoxin, which are associated with the episodic nature of FMF.
  9. IL-4 stimulated the induction of a monocyte hyporesponsive state to endotoxin in FMF patients.
  10. Colchicine was able to increase IL-4 synthesis in FMF monocytes.
  11. IL-4 is an anti-inflammatory cytokine.
  12. Endotoxin tolerance induction occurs in FMF patients during an acute FMF attack. It could be an adaptive response of monocytes to protect from unwanted immune reactivity in the inflamed tissue during the resolution phase, where they downmodulate subclinical immune activation and inflammatory reactions in the FMF period of remission.

Newer Potential Treatment Options

  1. Anakinra (Kineret® injection) – a recombinant human interleukin-1? receptor antagonist used in human patients with CAPS and FCAS.
  2. Etanercept (Embrel® injection) – a TNF inhibitor. P75 TNFR:Fc fusion protein. This has been used in human patients in TRAPS. In some human patients this drug even appears to prevent amyloid formation.

Fibrillex™ — Neurochem

  1. Highly sulfated proteoglycans are common constituents of amyloid deposits in all known types of amyloidosis so far. These proteoglycans, more specifically the sulfated glycosaminoglycan (GAG) molecule portion of specific proteoglycans, have been shown to interact with the amyloidgenic amyloid proteins. These GAGs promote fibril formation.
  2. Neurochem has the ability to design and synthesize small organic molecules that mimic the sulfated GAG molecules. These therapeutic molecules, called “GAG mimetics”, inhibit the fibrillogenesis process.
  3. These “GAG mimetics” compete with the natural GAGs for the same binding sites on the amyloid proteins, preventing the association of natural GAGs with the protein. By preventing natural GAGs from binding to the amyloid proteins, the “GAG mimetics” can prevent fibril formation.
  4. Fibrillex™ — 1,3-propanedisulfonate (1,3 PDS).
  5. Recent name change to Kiacta™ (eprodisate).

New Diagnostics

  1. A new diagnostic procedure in humans for the diagnosis of amyloidosis is subcutaneous fat aspiration with Congo red staining.
  2. Sensitivity of the technique ran 80-93% with a specificity of 100%.
  3. If results of fat tissue aspiration are negative, the additional value of a subsequent tissue biopsy is negligible.
  4. Van Gameren I, Hazenberg B, Bijzet J, Van Rijswijk M. Diagnostic accuracy of subcutaneous abdominal fat aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis Rheum 54:724-729 (2006)


  • Stojanov S, Kastner D. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rhuematol 17:586-599, 2005.
  • Martinon F, Burns K, Tschopp J. The Inflammasome: A Molecular Platform Triggering Activation of Inflammatory Caspases and Processing of proIL-?. Molecular Cell, Vol. 10, 417-426, August, 2002.
  • Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature Vol. 440, 237-241, 2006.
  • Bakkaloglu A, Duzova A, Ozen S, Balci B, Besbas N, Topaloglu R, Ozaltin F, Yilmaz E. Influence of Derum Amyloid A (SAA1) and SAA2 Gene Polymorphisms on Renal Amyloidosis, and on SAA/C-Reactive Protein Values in Patients with Familial Mediterranean Fever in the Turkish Population. J Rheumatol 2004, 31.6:1139-1142.
  • Davtyan T, Hakopyan G, Avetisyan S, Mkrtchyan N. Impaired Endotoxin Tolerance Induction in Patients with Familial Mediterranean Fever. Pathobiology 2006;73: 26-39.

I especially appreciate the dedicated work of Dr. Linda Tintle in this area and for her help and friendship over the years as we have served together on the Chinese Shar-Pei Club of America Health Through Education Committee.            

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