Page 564 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 38 Immune Deficiencies at the Extremes of Age 541

Infant Elderly
Up
TCR TCR
CD4 CD4 Down
Lck Zap70 Lck Zap70

PLC pERK DUSP6

miR-181a
T cell activation T cell activation
Internal changes
Telomere length +++ +
DNA damage + +++
Epigenetic modifications + +++
Functional outcomes
Proliferation capacity +++ ++*

T cell activation + +
Effector function + +*
+ = low ++ = normal +++ = high *controversial
fIG 38.4 Intrinsic Differences in CD4 T Cells at the Extremes of Age. CD4 T cells from infants
and older individuals demonstrate similar dysfunctions, including poor activation and reduced
effector functions, although as a result of distinct mechanisms. Signaling cartoons illustrate the
best documented defects. Moreover, infant and older adult T cells have very different internal
changes to their DNA, including telomere length, the amount of DNA damage, and epigenetic
modifications.

KEY CoNCEPtS activation of naïve T cells. Changes in cell surface molecules
Cellular Dysfunction With Age that are seen with terminal differentiation, such as the gain in
CD57 and the loss of CD27 and CD28 expression, are the most
• Exposure to aging host environment (e.g., inflammatory cytokines) striking. Of functional importance, predominantly for CD8 T
activates negative regulatory signaling loops. cells, is the gain in expression of cell surface receptors that are
• Telomeric erosion impairs proliferative competence and restraints usually only found in NK cells. Most of these receptors have
clonal expansion. inhibitory function, but some of them also stimulate. Since
• End-differentiation reduces functional plasticity. expression of these receptors on individual cells is stochastic,
• Activation of specific gene programs modifies cell function: the consequences can range from immunosuppression to
• Gene programs associated with differentiation (e.g., microRNA
[miRNA]) autoreactivity.
• Gene programs associated with T-cell exhaustion (e.g., expression
of programmed death-1 [PD-1])
• Loss of CD28 on T cells CLINICAL CONSEQUENCES OF IMMUNE AGING—
• Gain in natural killer (NK) cell–associated regulatory receptors on IMMUNODEFICIENCY, AUTOIMMUNITY, AND
T cells (e.g., killer immunoglobulin-like receptor [(KIR], killer lectin-like
receptor [KLR], immunoglobulin-like transcript [ILT]) ACCELERATED DEGENERATIVE DISEASES
• Senescence-associated gene activation (e.g., inflammatory
mediators) The most profound and most noted consequence of human
senescence is the increased susceptibility to infections. Upper
respiratory bacterial and urinary tract infections are frequent in
the older population and less contained by the innate immune
example is the acquisition of memory-like and effector phenotypes system and preexisting adaptive immunity. Not surprisingly, the
with lymphopenia-induced homeostatic proliferation. So-called immune system of an older adult is not able to induce a protective
virtual memory cells, which presumably have never seen an response to new antigens to which the individual has not been
exogenous antigen, have been identified in mouse models; clonal exposed to in the past. Clinically important examples are the
expansions are also seen within the human naïve T-cell compart- severe acute respiratory syndrome (SARS) epidemic and West
ment. Some of the changes in gene expression that are seen in Nile fever virus infection. First-time vaccinations with live viruses,
naïve T cells with age may represent partial differentiation, such for example, yellow fever virus, are associated with increased
as declines in the microRNA miR181a and changes in the expres- morbidity and even mortality in older adults. Despite annual
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sion of phosphatases and other signaling molecules. Increased vaccination, influenza infections continue to be associated with
expression of cytoplasmic phosphatases impairs the TCR-induced high morbidity and mortality. Pneumonia caused by RSV, usually