Page 998 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 71 Type 1 Diabetes 963

The Environment
Th he e e E
T T T Th
h h has
has Changed
Excess calories *
Different, less diverse food
Less physical activity *
Less sunlight-vitamin D *
More ‘hygiene’ *
Fewer infections
More C-sections *
Less breast milk *
More antibiotics *
Less thermoregulation
Less sleep
More pollution

Modifiers: culture,
education, wealth, access
to technology, family size,
maternal age...
FIG 71.6 Changes in the modern environment. Those that have been associated with an increased
risk for type 1A diabetes (T1DA) in humans or nonobese diabetic (NOD) mice are indicated
(marked *).

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found in children at risk for T1DA. Diets containing a diverse enteroviruses in T1DA but has not been consolidated in follow-
range of plant products (cereals, fresh fruits, and vegetables) up studies. Even if a particular enterovirus strain were shown
provide complex carbohydrates for fermentation by colonic directly to be diabetogenic, vaccination would be elusive because
bacteria to short-chain fatty acids (SCFAs), which are antiinflam- among the many thousands of strain variants, the only one for
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matory. The dramatic influence of the environment is seen in which a vaccine exists is poliovirus. Mumps virus epidemics
the comparison between the highly developed Finland and the have been associated with T1DA onset after 2–4 years, and
nearby undeveloped Russian Karelia. Finland has the highest introduction of a mumps vaccine was associated with a plateau
incidence of T1DA in the world, currently 57.6 cases/100 000 in the rising incidence of T1D in Finland, but this was temporary,
population ≤14 years of age (www.diabetesatlas.org). In 2005, and mumps vaccination has clearly not prevented T1D. It must
there was a sixfold difference in the incidence of T1DA between be emphasized that there is no scientific evidence that any form
Finland and Karelia despite overlap in ethnic background and of vaccination itself triggers T1DA.
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a similar distribution of HLA-DQ risk genotypes. This difference Rotavirus is the commonest cause of gastroenteritis in young
could reflect a relatively lower rate of infections (in Finland), in children. The discovery of strong sequence similarities between
keeping with the “hygiene hypothesis.” 29 T-cell epitopes in the VP7 protein of rotavirus and the IA2 and
However, viral infections have long been considered triggers GAD islet antigens in autoantibody-positive children led to
of T1DA, but the evidence remains inconclusive. 30,31 Viral infection speculation that mimicry of rotavirus might contribute to islet
is circumstantially associated with the onset of T1DA, but given autoimmunity. Subsequently, in the Australian BabyDiab Study,
the long presymptomatic stage of the disease, this may simply rotavirus infection was associated over time with the first appear-
represent a nonspecific inflammatory insult that precipitates ance of or an increase in islet autoantibodies in children before
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clinical presentation. Viral mechanisms in T1DA could be direct they developed diabetes. Moreover, rotavirus has been shown
or indirect (e.g., infection of β cells, infection of the exocrine to infect β cells in islets from mice, pigs, and monkeys and cause
pancreas with bystander death of β cells, mimicry between T-cell transient involution of the pancreas and hyperglycemia in a
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epitopes in a viral protein and β-cell autoantigens, or activation Toll-like receptor 3 (TLR3)–dependent manner in mice.
of endogenous retroviruses in β cells by environmental agents). Ubiquitous rotavirus infections that drive cross-reactive immunity
If an exogenous virus was clearly identified, then protective to islet autoantigens are unlikely to be diabetogenic but could
vaccination early in life would be an approach to primary preven- complement and sustain the immune response to direct infection
tion. Interest in viral triggers of T1DA was initiated by the of β cells. As with rubella and mumps, it will be interesting to
observation that a minority of children with congenital rubella observe if recently introduced rotavirus vaccines have any effect
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developed insulin-dependent diabetes and were found to have on the incidence of T1DA.
a higher frequency of what was later recognized as the T1D The microbiome—the trillions of microorganisms (bacteria,
susceptibility haplotype HLA-A1 B8-(DR3-DQ2). Clearly, this fungi, archaea, protozoa, and viruses; Chapter 14) and their
may have been an anomaly because congenital rubella has been millions of genes and proteins that reside within the human
virtually eliminated by vaccination and yet the incidence of T1D mucosae, skin, and secretions—has gained increasing atten-
has continued to climb. Much circumstantial evidence exists for tion as a bellwether of health and disease (“dysbiosis”). Most