Page 999 - Clinical Immunology_ Principles and Practice ( PDFDrive )

964 Part seven Organ-Specific Inflammatory Disease

microbiome analyses are based on DNA extraction and poly- on a limited scale and at considerable cost to individuals with
merase chain reaction (PCR) amplification of regions of the 16S T1DA and life-threatening complications, in particular lack of
ribosomal RNA (rRNA) gene that are conserved among bacteria. awareness of hypoglycemia that is unresponsive to conventional
Although other internal regions of the 16S gene are variable treatment. However, shortage of donor tissue, cost, and the need
and enable taxonomic classification from the phylum to genus for life-long immune suppressive agents militate against this
level, 16S sequencing does not have the sensitivity to distinguish solution. Longer-term, genetically engineered pig islet xenografts
individual species and their strains. Direct metagenomic sequenc- may overcome the tissue supply barrier. Stem cells, in particular
ing of all species, as well as analysis of their transcriptomes, autologous induced pluripotent stem cells (iPSCs), remain the
epigenomes, and functions, is required to fully comprehend the great hope, but early proof-of-concept results in rodents await
role of the microbiome in T1DA and other chronic immune– scale-up and translation to humans.
inflammatory diseases. The marked difference in the incidence The incidence of spontaneous autoimmune diabetes in
of T1DA between Finland and neighboring Karelia was found inbred NOD mice is decreased by many immune and other
to be associated in Finnish children having decreased bacterial (including environmental) interventions introduced early in the
diversity overall, a dominance of the phylum Bacteroidetes, and disease course, although various interventions are often only
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lack of butyrate-producing bacteria. These changes were seen effective in a proportion of mice, sometimes only delay disease
after the appearance of autoantibodies, suggesting that they onset, and sometimes have no effect (and are therefore not
followed, rather than preceded, the disease process. However, reported). Nevertheless, these findings in the NOD mouse suggest
in a further small study in Finnish children, metagenomic that T1DA is potentially preventable in outbred humans. On
sequencing identified a relative abundance of Bacteroides dorei, the basis of the key role of proinsulin in driving β-cell autoim-
which peaked around 7–8 months of age with the introduction of munity, the NOD mouse has provided “proof-of-concept” for the
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solids and preceded the appearance of islet autoantibodies. Gut efficacy of antigen-specific vaccination strategies. In humans,
Bacteroides species are abundant in Finnish children, including it has been convenient to classify prevention into primary
B. dorei, which produces a lipopolysaccharide (LPS) endotoxin (before the onset of islet autoimmunity), secondary (after
that inhibits the immunostimulatory activity of Escherichia coli the onset of islet autoimmunity), and tertiary (after the onset
LPS, known to protect against development of diabetes in NOD of clinical disease) prevention. Of course, real prevention is
mice. These findings suggest that an approach to lowering the primary prevention—identifying those at genetic risk and inter-
environmental contribution to T1DA will be intervention with vening to avert islet autoimmunity. Neonatal screening based
prebiotics, probiotics, or other means to favorably alter the on HLA genotyping to identify at-risk individuals would be
composition of the gut microbiome. a basis for primary prevention, but even in countries with a
high incidence of T1DA, this would have only modest predictive
KeY COnCePts value, and intervention could be justified if it was practical and
Type 1A Diabetes: Epidemiology, Environment, safe, if not efficacious. The mandate Primum non nocere (“first
do no harm”) dictates that many immune modulating agents
and Genes are off limits for either primary or secondary prevention in
• Incidence is increasing as a result of the impact of environment. T1DA. Options (e.g., to modification of the diet or microbi-
• Environment factors enable increasing penetrance of lower-risk human ome or of forms of vaccination) are greatly restricted. Agents
leukocyte antigen (HLA) alleles. that are effective in other autoimmune diseases are more
• Environmental factors are multifactorial but generally “pro-inflammatory” likely to be effective in the early asymptomatic stage of T1DA,
and impact via microbiome dysbiosis and epigenetic modifications on not after clinical presentation when most β cells have been
polygene expression to cause immune dysregulation in early life. destroyed. Indeed, clinical trials of tertiary prevention with
more than 70 different agents since the early 1980s have failed
TREATMENT AND PREVENTION to unequivocally demonstrate sustained preservation of residual
β-cell function. 36,37 Interestingly, the number of trials reporting a
Treatment of the metabolic syndrome of T1D is focused on positive outcome decreased from the 1980s, together with a shift
optimizing blood glucose control with various modes of insulin in the primary outcome measure away from clinical remission
delivery to prevent the short- and long-term complications of to the more rigorous measure of residual insulin (stimulated
hyperglycemia. Refinements and advances over the past 30 years C-peptide) secretion.
in insulin delivery and improved control of blood glucose and Is there a potential solution to the “off limits” dilemma? Classi-
blood pressure have greatly improved the lives and prognosis of cally, T1DA is regarded as a metabolic disorder diagnosed at clinical
individuals with T1DA. Nevertheless, despite the introduction presentation with symptoms and signs of hyperglycemia. However,
of pure, recombinant forms of human insulin, which have varied based on pathology, T1DA is an immune disease—autoimmune
kinetics of action and can be injected via a syringe or continuously β-cell disorder (ABCD)—and only becomes a metabolic disorder
infused via a pump, and blood glucose self-monitoring, which at the end stage of its pathology. Accepting this reality would
can now be done continuously in real time, those with T1DA amount to a paradigm shift that could profoundly change the
have not been rescued from a life sentence, and their blood approach to and outcome of secondary prevention. Consider the
glucose control remains less than physiological. The “cure” of situation in other autoimmune diseases. In rheumatoid arthritis,
T1DA requires the transplantation of insulin-secreting cells or the pathology and clinical features (painful swollen joints) appear
their progenitors or the regeneration of β cells in situ, in conjunc- concomitantly when effective disease-sparing treatment with
tion with approaches to prevent allograft rejection and/or newer biological agents is initiated, not at the end stage of pathol-
recurrence of autoimmunity (there will be no cure for T1DA ogy when the joints are irreversibly deformed. A further benefit
without prevention). Currently, in some economically developed of diagnosing of T1DA early in the asymptomatic stage, based
societies, allografts of whole pancreas or isolated islets are offered on evidence of underlying pathology, is that it would markedly