section 35.10
Complement
827
In addition to V gene recombination and class switch-
ing, Ig genes are alternatively spliced following transcrip-
tion. Introns are spliced out of the RNA as expected, but the
p,
chain gives rise to both the pentameric, IgM molecules
and the membrane-bound monomeric form of IgM. A re-
gion of the heavy chain gene that codes for constant re-
gions of the polypeptide chain (the switch region) is the
sequence within which alternative splicing occurs. IgD
heavy chain variation also results from alternative splic-
ing of RNA transcripts.
35.9 Major Histocompatibility Complex (MHC)
Genes
The antigen-presenting proteins encoded by genes of the
major histocompatibility complex have been described
above. These proteins and the genes that code for them
are highly polymorphic, but not because of the mecha-
nisms that generate B- and T-cell diversity. The variability
in MHC gene products is derived primarily from gene
polymorphisms—different alleles carried by individuals
in a population. Allelic exclusion does not occur with the
MHC genes; thus, an individual has genes (haplotypes)
contributed by both parents. Historically, the MHC I and
II gene families were identified based on transplanted tis-
sue compatibility and are alternatively known as HLA I
and HLA II gene clusters.
The major histocompatibility genes (on chromosome
6
)
comprise a cluster that encode the class I and class II
proteins (MHC I and MHC II) and some of the comple-
ment proteins (MHC III). A fourth group, the MHC IV
genes, has been proposed. These additional genes encode
at least three proteins associated with inflammation:
tumor necrosis factor
a
(TNF-a) and the lymphotoxins
TNF-/-S and TNF-y. The histocompatibility genes are the
most polymorphic genes known and thus they create a
major challenge that is associated with donor/recipient
matching for organ transplantation. In contrast to the
immunoglobulin and T-cell receptor genes, the MHC
genes do not undergo rearrangements; the polymorphisms
are due to the different alleles (more than
1 0 0
for the
MHC I heavy chain gene).
Transplant rejection is an example in which the distinc-
tion between self and nonself works to the disadvantage of
the transplant recipient and provides the most formidable
challenge facing transplantation medicine.The MHC and
other cell surface proteins of the transplant are foreign to
the receipt and thus are targets for antibodies, T cells, and
phagocytes. This recognition of the transplanted cells and
organ(s) as nonself initiates the immune response. Attack
on the transplanted tissues then leads to destruction
(rejection) of the organ. Complement activation also
occurs, which both enhances the destructive process and
produces additional biological effects that are caused
by complement-derived products (see “Complement”).
Immunosuppressive drugs, although they make transplan-
tation possible, create risk to the recipient because they in-
crease susceptibility to infection. Two immunosuppressive
drugs, cyclosporin A and FK506 (tacrolimus), suppress
the production of the interleukin (IL-2) and thus, because
IL-2 is necessary for T-cell growth (see Table 35-4), sup-
press T-cell proliferation. This is accomplished through
the binding of these drugs to a class of proteins called
immunophilins.
The immunophilin-bound cyclosporine A
or FK506 inhibits calcineurin, a protein phosphatase
that is involved in the T-cell receptor signaling pathway
protein transcription. The structures of FK506 is shown in
Figure 35-21. Humanized monoclonal antibodies have
been developed that successfully reduce the rejection
of transplanted organs. One such monoclonal antibody,
OKT3, is directed to the T-cell antigen CD3. Binding
to OKT3 renders the T cells incapable of function-
ing. Perhaps the most exciting discovery relevant to
transplantation is that cytokines and other growth fac-
tors can direct host stem cells to produce tissues and
organs that are immunologically compatible with the
host.
MHC genes also determine the susceptibility of in-
dividuals to autoimmune diseases. Among the diseases
clearly related to MHC genes are insulin-dependent di-
abetes,
multiple sclerosis, systemic lupus, erythemato-
sus, myasthenia gravis,
and
rheumatoid arthritis.
Alle-
les of MHC genes are also associated with non-immune
system diseases, e.g.,
hemochromatosis, narcolepsy,
and
dyslexia.
35.10 Complement
The complement system, part of the innate immunity of
animals, provides the third defense mechanism against in-
fectious agents, the first and second being the physical
barriers provided by skin and the mucous secretions. The
complement system consists of more than 30 proteins that
circulate as well as complement receptors and comple-
ment control proteins. There is no simple mnemonic for
understanding the nomenclature of the complement sys-
tem components. Some—but only some—of the comple-
ment proteins are designated by an uppercase letter C fol-
lowed by a number, e.g., Cl -C9. Complement proteins (C)
that have been proteolytically cleaved are distinguished by
lower case letter following the C-number, e.g., C3b, C3a,
etc. Table 35-3 contains the list of complement proteins
along with a description of some of the pertinent chemical,
physical and physiological properties of each component.
