Immune regulation by microRNA implications for diagnosis and treatment of chronic disease development in aging people with rheumatoid arthritis (RA) and osteoarthritis (OA) as disease models.

Many chronic diseases with an increased prevalence in elderly are known to
cluster and have a strong relation with characteristic, complex, changes in the
immune response which may occur as a result of aging. Specifically,
immunological aging is presumed to be causally related to autoimmunity, cancer,
cardio vascular disease (including atherosclerosis), sarcopenia, Alzheimer*s
disease, diabetes, a generally increased vulnerability to infection and a
decreased responsiveness to vaccination. The age dependent deterioration of the
immune function (immunosenescence) is characterized by a reduced CD4/CD8 T-cell
ratio, loss of costimularory and proliferative capacity and increased
production of pro- and anti-inflammatory cytokines. Collectively, these
phenotypic age related changes are denoted by the term *immune risk
profile* (IRP).
A better understanding into the nature of risk factors as well as the
association of risk factors, such as IRP, with multi-morbidity is central for
improvement of treatment, early diagnosis and prevention of chronic diseases.
In this respect, two important issues need to be addressed: First, how can
patients at risk be recognized, e.g. what are the indicators that relate to the
development of IRP and multi-morbidity. Second, what are the mechanistic
fundaments of the age related aggregation of risk factors, e.g. what age
related molecular mechanisms are instrumental for the development of an IRP and
co-morbidity.
In respect to the first issue, indicators aimed at the identification of
patients at risk for multi-morbidity or complex care, such as provided by the
Groningen Frailty Indicator (GFI), provide an easy and inexpensive basis for
the standardized screening of patients at risk for the development of multi-
and co-morbidity such as possibly associated with immunosenescence. As such, it
would be most relevant to investigate immunological characteristics of elder
individuals that present with a high GFI. In respect to the second issue, one
class of molecules, so-called microRNAs (miRNAs), are of specific interest.
MiRNAs are endogenous small RNAs (approximately 22 nucleotides) that have
recently emerged as key factors in regulating and fine-tuning homeostatic
cellular processes such as fundamental to a proper functioning immune response.
Specifically, recent studies have shown the profound impact of miRNAs on immune
receptor responsiveness, cytokine production and germinal centre formation,
underlining the importance of miRNAs in immunocompetence. In general, miRNAs
are important epigenetic regulator molecules involved in normal tissue
development and cell biological processes. miRNAs act by controlling protein
expression at the level of mRNA protein translation. By complementary pairing
with specific target mRNAs in their 3* untranslated region (3*UTR), miRNAs
allow translational repression and/or degradation of the target mRNA and, as
such, protein expression. The differential expression of miRNAs in, sometimes,
closely related subsets of cells and their differential expression through
developmental stages of cells and tissues is now recognized as an important
epigenetic factor in normal and patho-physiological aspects of aging, including
immunological aging. E.g. disregulation of miRNA expression results in
lymphomagenesis and immunosenescence. Thus, miRNAs may be regarded both as
phenotypically relevant biomarkers, specifically for complex, chronic, age
related morbidities, and leads for therapeutic intervention.

In this project we will set out to investigate characteristics of the aged
immune response, with a particular focus on the role of microRNAs (miRNAs)
herein. Specifically we will address two aims:
1) We aim to characterize the differences in the miRNA profile of immune cells
associated with an IRP in relation to multi-morbidity (part 1 of the study).
2) We aim to delineate how miRNAs associated with patho-immunological aspects
of aging relate to the devlopment of multimorbidity. (part 2 of the study).

Observational study with assessment of microRNA in blood.

The burden for patients lies in the fact that during regular visits at the
outpatient clinic they have to fill in questionnaires and extra blood will be
drawn during regular vena puncture. For healthy controls the burden lies within
the fact that they have to visit the outpatient clinic, fill in questionnaires
and have a vena puncture. To decrease their burden we will recruit as much as
possible HC by asking partners of patients if they are willing to participate
in the present study.