Biomedical Engineering Reference
In-Depth Information
to its surface receptor on polymorphonuclear neutrophils induces increased
expression of the gene coding for a neutrophil cell surface protein capable of binding the F c por-
tion (i.e. the constant region; see also Box 13.2) of IgG. This greatly increases the phagocytotic
and cytotoxic activities of these cells.
IFN-
Binding of IFN-
γ
also directly modulates the immune response by affecting growth, differentiation and
function of both T- and B-lymphocytes. These effects are quite complex and are often infl uenced
by additional cytokines. IFN-
γ
acts as a growth factor in an autocrine manner for some T cell
sub-populations, and it is capable of suppressing growth of other T cell types. It appears to have
an inhibitory effect on development of immature B-lymphocyte populations, but it may support
mature B cell survival. It can both up-regulate and down-regulate antibody production under vari-
ous circumstances.
All interferons promote increased surface expression of class I MHC antigens. Class II MHC
antigen expression is stimulated mainly by IFN-
γ
(MHC proteins are found on the surface of vari-
ous cell types. They play an essential role in triggering an effective immune response against not
only foreign antigen, but also altered host cells). Although many interferons promote synergistic
effects, some instances are known where two or more interferons can oppose each other's biologi-
cal activities. IFN-
γ
A-mediated stimulation of NK cells.
The molecular basis by which interferons promote their characteristic effects, in particular
antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway
induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral
replication. These antiviral gene products are generally enzymes, the most important of which are
2
α
J, for example, can inhibit the IFN-
α
protein kinase.
These intracellular enzymes remain in an inactive state after their initial induction. They are
activated only when the cell comes under viral attack, and their activation can inhibit viral replica-
tion in that cell. The 2,5-A n synthetase acts in concert with two additional enzymes, i.e. an endori-
bonuclease and a phosphodiesterase, to promote and regulate the antiviral state (Figure 8.4).
Several active forms of the synthetase seem to be inducible in human cells; 40 kDa and 46 kDa
variants have been identifi ed that differ only in their carboxy terminus ends. They are produced as
a result of differential splicing of mRNA transcribed from a single gene found on chromosome 11.
A larger 85-100 kDa form of the enzyme has been detected, which may represent a heterodimer
composed of the 40 and 46 kDa variants.
The synthetase is activated by double-stranded RNA (dsRNA). Although not normally present
in human cells, dsRNA is often associated with commencement of replication of certain viruses.
The activated enzyme catalyses the synthesis of oligonucleotides of varying length in which the
sole base is adenine (2
-5
oligoadenylate synthetase (2,5-A n synthetase) and the eIF-2
α
A n ). This oligonucleotide differs from oligonucleotides present naturally
in the cell, in that the phosphodiester bonds present are 2
-5
bonds (Figure 8.5). The level of syn-
thesis and average polymer length of the oligonucleotide products appear to depend upon the exact
inducing interferon type, as well as on the growth state of the cell.
The sole biochemical function of 2
-5
A n synthetase) appears to be as an
activator of a dormant endo-RNase, which is expressed constitutively in the cell. This RNase,
known as RNase L or RNase F, cleaves all types of single-stranded RNA (ssRNA). This inhibits
production of both viral and cellular proteins, thus paralyzing viral replication. Presumably, cel-
lular destruction of the invading ssRNA will be accompanied by destruction of any additional
viral components. Removal of dsRNA would facilitate deactivation of the endo-RNase, allowing
translation of cellular mRNA to resume. A 2
-5
A n (and hence 2
-5
-5
phosphodiesterase represents a third enzymatic
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