Page 734 - Clinical Immunology_ Principles and Practice ( PDFDrive )

706 Part SIX Systemic Immune Diseases

KEY CONCEPtS lower androgenic testosterone and dehydroepiandrosterone
Important Risk Factors for Developing (DHEA) levels, and increased estradiol, compared with healthy
control male subjects.
Rheumatoid Arthritis
• Female gender; impact of X chromosome, microchimerism, ETIOLOGY AND PATHOGENESIS
lifestyle
• Age; associated with accelerated immune aging Environmental and Nongenetic Factors
• Inheritance of genetic variants, e.g., HLADRB1 and PTPN22 Most, but not all, studies have reported an association between
• Autoantibodies to citrullinated protein antigens (ACPAs), rheumatoid RA and smoking. One of the largest studies comprising over
factor 370 000 women from Women’s Health Cohort Study reported
• Family history; first-degree relatives have higher prevalence of genetic
and serological risk factors a relative risk of 1.4 for women who smoked more than 25 ciga- 8
• Hormonal factors; nulliparity, the first 3 months postpartum, low rettes per day for more than 20 years, compared with nonsmokers.
androgen or high estrogen status (in males); longer-duration The association appears to be more closely related to duration
breastfeeding than to the amount of tobacco exposure, with smoking status
• Smoking status; >25 cigarettes/day for >20 years confers a 15-fold being a risk factor for older age of RA onset; smoking also may
9
risk in subjects who carry disease associated human leukocyte antigen influence severity because smokers are more likely to have
(HLA)-DRB1 alleles
• Low alcohol intake seropositive, erosive disease with extraarticular manifestations.
• Environmental antigens (the “exposome”); dietary factors; exposure The effect may be fully reversible in those individuals who stop
to infectious (and noninfectious/microbiota) pathogens at mucosal smoking for 10 years or more. Further evidence of gene-
surfaces such as the lung, periodontium, and gut; noninherited maternal environment interactions with respect to smoking have been
antigens (NIMA) documented in a population-based case–control study of Swedish
• Urban dwelling RA patients. In this study the relative risk of developing
10
+
rheumatoid factor (RF) positive (RF ) RA was calculated according
to smoking status and HLA-DRB1 genotype. The relative risk
of developing RA increased from 2.5 in nonsmokers with disease-
Two of the more intriguing factors contributing to disease associated HLA-DRB1 genes to 7.5 and 15.7 in smokers who
occurrence are age and gender. Age-associated changes in sus- carried one or two copies of the susceptibility alleles, respectively.
ceptibility to infection, neoplastic disease, and autoimmunity Follow-up gene-environment interaction studies demonstrate
suggest that a common mechanism could be responsible. Immune robust associations between heavy smoking, HLA-DRB1 alleles
senescence is one possibility, where age-related decline in host encoding specific amino acids at positions 11 and 13, and the
immunity is characterized at the cellular and molecular level by presence of ACPAs. Strongest associations were with antibodies
dramatic expansions of lymphocyte clones, corresponding to citrullinated α and β chains of fibrinogen (epitopes Fibα580–600
contractions of the naïve T- and B-cell repertoires, and telomere and Fibβ36–52) and α-enolase (CEP-1); IgA ACPAs were especially
erosion of leukocytes, indicative of an extensive proliferative prevalent in smokers.
6
history. When combined with oxidative stress and a range of Being female, a smoker, and carrying specific disease-associated
biochemical derangements of pathways integral to antigen genetic variants may be necessary but not sufficient to initiate
responsiveness and immune regulation, these factors may combine chronic inflammatory arthritis. Other environmental triggers
to (i) increase susceptibility to foreign pathogens, (ii) augment may be involved. Not least among these is exposure to foreign
reactivity to self-tissue antigens (which may be modified post- pathogens. This association has gained credibility because of the
translationally by the aging process), and (iii) generate a repertoire presumed link between not only infection and autoimmunity
of lymphocytes defective in terms of tumor surveillance. Thus but also immunodeficiency and autoimmune disease. Nonetheless,
immune senescence could be considered a risk factor for RA. no single pathogen or group of pathogens has been defined.
The female sex preponderance implies that hormonal and This could imply that aberrant host responses (either exaggerated
reproductive factors strongly influence risk. On the one hand, innate inflammatory responses or failure to terminate such
nulliparity is a risk factor for RA. Women entering the first 3 responses) may arise after a wide range of infectious insults.
months of the postpartum period are also at increased risk. By Indeed, bacterial products including superantigens, mycoplasma
contrast, oral contraceptive use, pregnancy, and hormonal species, viruses (including herpes family, parvovirus, and retro-
replacement therapy have all been associated with reduced risk viruses), and fungi have all been implicated, but data are insuf-
7
or less severe disease, whereas extended periods of breastfeeding ficient to prove causation. Epstein-Barr virus (EBV) infection
appear to increase risk. Several possible immune mechanisms is common, antibodies to EBV nuclear antigens have been reported
have been proposed. For example, maternofetal mismatch at the in patients with RA, EBV is a polyclonal activator of B lympho-
major histocompatibility complex (MHC) locus has been associ- cytes, EBV-specific T cells reactive to EBV gp110 have been
ated with higher disease remission rates during pregnancy. In identified in RA synovial joints, and EBV RNA has been isolated
contrast, noninherited HLA-DRB1 DERAA-positive (occupying from the synovium. There exists a tantalizing link between
the same amino acid positions as the QQRAA/QKRAA/KKRAA infection with Porphyromonas gingivalis, which expresses its own
shared epitope motif) maternal antigens (NIMA) expressed on enzymatic machinery for generating bacterial or host-derived
maternal cells constitute an environmental factor that is protective citrullinated proteins, severe periodontitis (which shares risk
11
to a DERAA-negative child, perhaps through mechanisms relating factors for RA), and RA. According to this model, molecular
to microchimerism. In mouse models pregnancy has been mimicry is underpinned by autoimmune responses to bacterial-
associated with quantitative changes in the numbers of regulatory derived proteins such as enolase and cross-reactivity to the human
T cells (Tregs). An influence of hormonal factors is further orthologue α-enolase, expressed in abundance by myeloid cells
suggested in studies of men where disease is associated with in inflamed periodontal and synovial tissues.