Page 752 - Clinical Immunology_ Principles and Practice ( PDFDrive )

724 Part six Systemic Immune Diseases

TABLE 53.1 Clinical and Laboratory Features of the Juvenile idiopathic arthritis
(Jia) Categories

Jia
Classifications Former Juvenile rheumatoid arthritis (Jra) spondyloarthropathy
+
−
JIA categories/ Systemic RF polyarticular RF polyarticular Oligoarticular Psoriatic (early Enthesitis-related arthritis (ERA)
features (persistent & and late onset) (including ankylosing spondylitis (AS)
extended) and inflammatory bowel disease [IBD])
Human leukocyte DRB1*11 DRB1*08 DRB1*04 A2 DRB1*01 B27
antigen (HLA)
Gender Equal F≫M F≫M F≫M F>M M≫F
Age at onset Peak 2 years Dual peaks Teenage 1–3 years Dual peaks Teenage
Antinuclear antibody Rare Yes Yes Yes Yes Rare
(ANA)
Uveitis Rare Yes Yes Yes Yes Non-silent
Temporomandibular Yes Yes Yes Yes Yes Yes
joint (TMJ)
Enthesitis No No No No Older age Yes
Arthritis Erosive Symmetric Erosive Mixed Dactylitis Axial

in the development of sJIA are additional arguments to consider
sJIA as autoinflammatory rather than autoimmune.
In contrast, enthesitis-related arthritis (ERA) and psoriatic
JIA share one of the strongest known MHC associations, HLA-B27,
for any described autoimmune disorder. HLA-B27 is present in
70–90% of Caucasian children with ERA. Inheritance of ERA
follows an autosomal dominant pattern and is the only JIA
category likely to have similarly afflicted first-degree relatives.
The pathophysiological explanation for the association of
HLA-B27 remains unknown, but hypotheses vary from molecular
mimicry of pathogens presented by HLA-B27 (Chapter 50) to
8
the unfolded protein response. The remaining JIA categories
have all been linked to various other MHC proteins to lesser
degrees (see Table 53.1).
Non-HLA Associations
Genes outside of the MHC have also been linked to developing
FiG 53.1 Hemophagocytosis as Part of Macrophage Activation JIA. Genetic approaches have highlighted the importance of
Syndrome (MAS). A centrally located, vacuolated histiocyte is genetic differences in the development of JIA, but at most, 11%
5
pictured engulfing numerous nucleated immune cells and non- of the contribution can be linked to the MHC. Recent develop-
nucleated mature red blood cells. Wright stain at ×198 magnifica- ments in high-throughput genetic sequencing combined with
tion. (Courtesy of Dr. David Kelly.) the identification of densely present restriction fragment length
polymorphisms (RFLPs) throughout the human genome have
allowed for powerful new genetic approaches. These include
genome-wide association studies (GWAS) designed to identify
genes associated with a variety of disorders, including autoimmune
9
heterozygous, rather than homozygous, mutations in genes critical diseases, such as JIA. To date, several genes have been reported
for cytolysis. 7 to be associated with JIA. 5
Strong evidence that genetic factors contribute to JIA sus-
HLA Associations ceptibility include twin and family studies. Data from a JIA
For all other JIA categories, polygenic influences, including national registry revealed that monozygotic twin pairs have a
the major histocompatibility complex (MHC), contribute to higher-than-expected proportion of twins with JIA. Moreover,
disease pathology. The MHC is complex and densely packed siblings of children with JIA have as high as a 30-fold increased
(>200 genes) with immune-associated genes (Chapter 5). The risk of JIA compared with the general population. Interestingly,
MHC is also the most polymorphic region of the human genome siblings with JIA typically share the same JIA category, age of
5
and gives rise to MHC class I and class II genes, complement onset, and disease course. Polymorphisms in MHC class II genes
proteins, TNF, and others. The critical role of MHC proteins have been estimated to account for <20% of the recurrence risk
in preventing autoimmunity by shaping the T-cell repertoire of JIA in siblings and thus support the concept that JIA is a
(Chapter 8) likely explains why the MHC is the most consistently complex genetic trait. JIA likely shares general or common
and strongly associated genetic locus for most JIA categories. autoimmunity gene risk factors with many autoimmune disorders
However, weak MHC associations and lack of gender predilection but may also be influenced by specific JIA risk-associated genes. 9