Significant remodeling occurs in the adaptive immune system during aging. This includes age-related loss of CD28 expression, skewing immune repertoire to the memory phenotype, T cell clonal expansion, increased autoimmune antibody production, and altered cytokine expression. This is considered to be responsible, at least in part, for the inflammatory phenotype or “InflammAging”, poor immune response to vaccination, and overall immune functional decline observed in older adults. In the syndrome of frailty, increasing evidence supports significant alterations in the T cell compartment of the adaptive immune system. The first line of evidence comes from a post hoc
analysis of the data from a nested-case control study evaluating the relationship between T cell subsets and mortality in community-dwelling older women (45
). The results showed that frail older women had significantly higher counts of CD8+
T cells compared to non-frail older women (n=24) matched by age and major comorbidities (cancer, arthritis, diabetes, cardiovascular disease, hypertension, and hormone replacement therapy). While no difference was observed in CD4+
T cell frequencies between the two study groups, the frail group had significantly lower CD4+
ratio compared to the non-frail group.
The second line of evidence comes from studies in the Multi-center acquired immune deficiency syndrome (AIDS) Cohort Study (MACS) comprised of immunodeficiency virus (HIV) positive and negative gay men. In the MACS study cohort, Desquilbet and colleagues developed a frailty-related phenotype (FRP) which includes 4 of the 5 Fried’s frailty criteria with measured walking speed being substituted by self-reported difficulty in walking. The results showed that compared to HIV-uninfected men of similar age, ethnicity and education, HIV-infected men were more likely to have FRP for all durations of HIV infection (< 4, 4.01 – 8, and 8.01 – 12 years) prior to the era of highly active antiretroviral therapies (HAAT). In addition, among HIV serconverters, men HIV infected for ≤4 years had FRP prevalence comparable to HIV-uninfected men 10 years older (46
). A subsequent study in the MACS cohort demonstrated that CD4+
T cell count predicted the development of a FRP among HIV-infected men, independent of HAART use and plasma HIV viral load (47
). These findings suggest a role of CD4+
T cell dysregulation in the development of frailty in HIV infected patient population.
In addition, a pilot study in thirteen pairs of age, race, and sex-matched frail and non-frail older adults living in the community with mean age of 84 years (range: 72–94) has shown that frail participants had increased counts of T cells expressing chemokine CC receptor-5 (CCR5) compared to the matched non-frail controls (48
). The increase of CCR5+
T-cell frequencies in the frail elderly cannot be contributed to the frailty-associated CD8+
T-cell expansion as such an increase was also observed in the CD8+
T-cell compartment. In addition, there was a trend toward graded increase in CCR5+
T-cell counts across the frailty scores in the frail participants (48
T cells have a type-1 pro-inflammatory phenotype and contribute significantly to several inflammatory conditions (49
). Moreover, CCR5 is a well known co-receptor for type-1 HIV (HIV-1); active development of anti-CCR5-based therapies for HIV infection and AIDS has shown promising results (51
). Therefore, findings from this pilot study, if validated, suggest that anti-CCR5-based strategies can potentially be developed for the prevention or delay and treatment of frailty in older adults.
Information about potential B-cell alteration in frailty is extremely limited. Utilizing spectratype analysis of the immunoglobulin (CDR)3 region, a recent study evaluated and compared B-cell repertoire diversity between elderly participants from the Swedish NONA Immune Study and young adults (53
). The results showed an age-related decrease in B-cell diversity and a dramatic collapse of the B-cell repertoire in a subset of older individuals who were considered frail. However, details on how frailty was defined in that study were lacking. Ongoing studies indicate that frail older adults have significant impairment in their antibody response to influenza vaccination compared to the non-frail counterparts (Leng S, unpublished data). It is not clear, however, whether this impairment is caused by alterations in the B-cell compartment or secondary to the frailty-associated T-cell dysregulation.
In summary, emerging evidence suggests significant alterations in the adaptive immune system in frailty, particularly in the T-cell compartment, above and beyond age-related immune remodeling. Further investigations into B cell function and regulation in frailty are needed.