Page 804 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 57 Spondyloarthritis 775

2. Genes involved in CD8 T-cell function (RUNX3, EOMES, the other for the receptor activator of NF-κB (RANK). No
IL7R, ITGAL) evidence was found for an MHC contribution to radiographic
3. Genes involved in peptide processing and presentation (HLA-B, severity.
ERAP1, UBE2L3, NPEPPS, ERN1, ASAP2)
4. Genes involved in microbial sensing (CARD9, NOS2, NOD2,
IRGM) Infection
5. Genes involved in nuclear factor (NF)-κB (NF-κB) activation A role for triggering infections has been better documented
(TLR4, NOD2, NOTCH1, TNFAIP3) in SpA than in most other rheumatic diseases. In developed
6. Others (ZMIZ1, FCGR2A, KIF21B, SH2B3, TNFRSF1A, GPR65, countries, the most frequent type of ReA occurs following
SULT1A1, GPR35, BACH2, ICOSLG, NKX2-3) urogenital infections with Chlamydia trachomatis (endemic
The most consistent (and best replicated) association is ReA). Postdysenteric ReA, more commonly encountered in
with ERAP1, which acts as a molecular ruler in the ER in “less technologically advanced countries,” occurs after various
trimming peptides processed in proteasomes to optimal Shigella and Salmonella (especially S. typhimurium and S.
length of nine amino acids for MHC class I binding and enteriditis), Campylobacter jejuni and C. fetus, and, in Europe,
presentation. HLA-B27–negative patients with AS lack an Yersinia enterocolitica species. Microorganisms implicated in
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association with ERAP1, although an association with ERAP2 ReA share common biological features: (i) They can invade
is seen. mucosal surfaces and replicate intracellularly; and (ii) they
A number of genes whose products are operative in the Th17 contain lipopolysaccharide (LPS) in their outer membrane.
pathway have also been associated with AS susceptibility: the Of particular note, antigens from Salmonella, Yersinia, and
IL-23 receptor (IL23R), which pairs with the IL12RB1 gene Chlamydia have been found in the synovial tissues and fluids
product to confer IL-23 (but not IL-12) responsiveness on cells of patients with ReA, often many years after the initial infec-
expressing both subunits; prostaglandin E receptor 4 (PTGER4), tion. Although only bacterial fragments of the enteric pathogens
which stimulates dendritic cell (DC) production of IL-23 and, have been found, evidence for viable C. trachomatis and perhaps
in turn, Th17 expansion and is overexpressed in SpA synovium; C. pneumoniae have been demonstrated in several studies.
signal transducer and activator of transcription 3 (STAT3), a key Chlamydia and other organisms have also been reported in the
regulatory factor in Th17 responses; and IL-12β (IL12B), which joints of healthy individuals, and this has led to questioning
encodes the IL12p40 protein, a component of both IL-12 and of the pathogenic significance of these findings. Other data,
IL-23. however, support the likelihood that bacterial persistence plays
GWAS in psoriasis and PsA have identified over 60 genes an important role in ReA, including the finding of specific IgA
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implicated in disease susceptibility outside the MHC. These antibodies and synovial T-cell proliferation to the initiating
include genes in common with those for AS (IL23R, IL12B, infectious agent.
CDKAL1, and ERAP1, the last showing interaction with
HLA-Cw6 similar to that seen with HLA-B27). Detailing all
the non-MHC genes associated with psoriasis is outside the The Gut and Spondyloarthritis
scope of this chapter. Non-MHC genes implicated in PsA In studies from Belgium and from Scandinavia, up to 50% of
susceptibility include IL-1A, as well as the IL-2/IL-21 and the patients with AS have microscopic ileal inflammation seen on
IL-4/IL-13 gene complexes (both important in Th2-associated ileocolonoscopy. Moreover, two-thirds of patients with undif-
autoimmunity). ferentiated SpA have histological gut inflammation. Gut inflam-
The first gene to be implicated in IBD susceptibility was NOD2/ mation in AS appears to be immunologically related to that seen
CARD15, which accounts for about 20% of CD susceptibility in CD. These observations have raised the speculation that the
and whose protein product serves as a receptor for bacterial inciting event in the SpA may be a breakdown of the gut–blood
products in monocytes that transduces signals leading to NF-κB barrier to intestinal bacteria, although such has yet to be proven.
activation. A number of GWAS conducted since then have It has been established that patients with AS and their relatives
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implicated over 130 genes in IBD susceptibility, including 113 have increased intestinal permeability compared with healthy
for CD and 100 for UC, and at least 83 shared genes between controls.
CD and UC. The autophagy 16-like 1 gene (ATG16L1), which The bacterial population inhabiting human intestines,
is highly expressed in intestinal cell lines, is linked to CD sus- referred to as the gut microbiota (Chapter 14), is a vast
ceptibility. DCs from patients with CD with susceptibility variants microbial community. The number of bacteria in the human
in NOD2 or ATG16L1 are deficient in autophagy induction, gut outnumbers the cells in the body 10-fold, and they contain
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suggesting that these genes influence bacterial degradation and 100 times more genes than in the entire body. In fact, there
interact with the MHC class II antigen-presenting machinery. is a beneficial relationship between the gut microbiome and
What is especially striking is the number of genes shared in the human system. The human gut provides nutrients and the
common with the various types of SpA, suggesting a common microbiome provides metabolic and physiological capacities,
pathogenesis. which possibly affect the education of the adaptive immune
system. Many studies, from early antibody and fecal carriage
studies suggesting a role for gut Klebsiella pneumonia in the
Genes and Severity of SpA pathogenesis of SpA (which has not been confirmed by modern
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Disease severity in AS also has a hereditary component. By sequencing studies) to more recent findings showing an
defining severity on the basis of radiographic involvement, interplay between host genetics (e.g., HLA-B27) and intestinal
two genes have been identified in a large candidate gene bacterial composition and others suggesting a link between
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study. One was the gene for cyclooxygenase I (COX-I), the intestinal dysbiosis and SpA, are suggesting that upsetting the
target of nonsteroidal antiinflammatory drugs (NSAIDs), homeostasis between the gut microbiome and the host immune