Exploration of Immunity in Gaucher Disease

Activated lipid engorged macrophages are the hallmark for Gaucher disease (GD). The evidence
for this activation comes from the clinical finding of 1000-fold increase of serum
chitotriosidase, a chitinase specifically secreted from activated macrophages. While these
markers decrease with the initiation of therapy, they are not specific for organ
involvement. The mechanisms of this macrophage activation is unclear, however, the presence
of a non-specific inflammatory response (e.g. high sedimentation rate), poor wound healing
and insulin resistance in Gaucher patients point to its clinical relevance. The finding of
T, B and NK cell abnormalities in Gaucher patients also suggest either direct effects of GD
lipid metabolites or indirect mechanisms via macrophages. Therefore, understanding the
mechanisms of macrophage activation and the crosstalk with other immune cell types could
provide mechanistic insights for pathogenesis of GD.

The investigators hypothesize that in GD the mechanisms leading macrophage activation could
be related either directly to the accumulation of the lipid metabolites or through the
effects of other cells of the immune system. To determine the pathways leading to macrophage
dysregulation in GD, the investigators will evaluate the functional response of monocytes
isolated from GD patients and profile of T cell and NK cell subsets in peripheral blood of
these patients. The investigators will then assess whether macrophage dysfunction in GD is
caused by an primary alteration immune response (NK and T cells response) or secondary due
to the direct effects of substrate accumulation performing immunological profiling of GD
patient blood samples, and through functional assays. Identification of the immunological
basis of GD pathogenesis could lead to the development of both biomarkers and novel
approaches for therapeutic interventions to alleviate disease symptoms. In addition, our
studies will reveal novel effects of the accumulation of the lipid substrate in GD in
modulating macrophage and lymphocyte subsets.

Inclusion Criteria:

- History of Gaucher disease

- Nonspecific inflammatory response evidenced by an increased ESR or positive CRP

- Positive markers for autoimmune disorders such as ANA, RF

- Chronic inflammatory disorders such as inflammatory bowel disease

- NIDDM

- Otherwise would qualify for an immunological work-up such as opportunistic or unusual
infections such as atypical mycobacterial infections, unexplained lymphadenopathy.

Exclusion Criteria:

- Severe cognitive deficits impairing decision making

- Pregnant or nursing, as these conditions may alter immunologic profile

- History of Hepatitis B, C or HIV infections