The role of immune networks is to defend the body against foreign invasion.
Microbes such as bacteria invade the body and activate innate antibacterial
systems, such as the complement cascade. Polymorphonuclear leukocytes are
attracted to this activity and attempt to ingest the bacteria.
The surfaces of the body are protected by cells on duty much like a military
organization defends a country. The interior body surfaces are lined with a
moist mucous-secreting surface that senses and reacts to the ambient
environment. Antigens are protein molecules that are recognized by immune cells.
Any chemical can link to a protein and become an antigen. Immune sensors or
lymphoid tissues are present in the surface linings or mucosa of the intestine
and respiratory tract (MALT). These sensors are mast cells, macrophages and
mobile lymphocytes of both T and B varieties. B and T-helper lymphocytes can
only see antigen presented by macrophages and other antigen-presenting cells
The purpose of the surveillance is to detect and respond to foreign antigens.
In the gut, lymphocytes are also contained in follicles, the solitary lymphoid
nodules (SLN), found along the length of the intestine and in much of the upper
and lower respiratory tracts. SLNs sample the soluble and particulate matter
from the environment. The gut-associated lymphoid tissues (GALT) and the lung or
bronchus-associated lymphoid tissues (BALT) are sensing agents for the whole
body, identifying antigens for later detection by internal immune defenses. Both
GALT and BALT and SLNs, contain predominantly B cells in which the major
immunoglobulin classes synthesized are IgM and IgA.
Antigen Presenting Cells
Immune responses often begin with macrophages, dendritic cells and other
antigen-presenting cells (APC) that ingest process and then present antigens on
their surface. The antigen signal attracts other immune cells who recognize it
and are activated by it. Antigen is presented adjacent to the major
histocompatability complex (MHC) proteins on the surface of APCs. The details of
how APCs ingest, digest and then express foreign antigens are being worked out.
The antigen moves through the cell membrane and is incorporated into a phagosome
which interacts with acts endoplasmic reticulum, a protein transfer system that
moves the antigen via a transporter to a location in the cell where the antigen
binds to MHC class I molecules. The antigen-MCH complex is then moved thorough
the cell membrane to appear on the outside as a receptor.
Molecules on bacterial membranes activate toll-like receptors (TLRs) on
macrophages and dendritic cells. These cells respond by secreting
proinflammatory cytokines as well as proteins such as CD86 and CD40 that
activate other cells amplifying the original signals and exciting an
inflammatory cascade. Dendritic cells (DCs) discover antigens in peripheral
tissues and then migrate to the local lymph nodes, where they encounter CD4+ or
CD8+ T cells, which are activated by the presentation of antigen-derived
peptides in association with major histocompatibility complex (MHC).
DCs take up antigen through different receptor families, such as Fc receptors
for antigen-antibody complexes, C-type lectin receptors (CLRs) for
glycoproteins, and pattern recognition receptors, such as Toll-like receptors
(TLRs), for microbial antigens. Geijtenbeek et al suggested that:” DCs are
continuously sampling and presenting self- and harmless environmental proteins
to silence immune activation. Uptake of self-components in the intestine and
airways are good examples of sites where continuous presentation of self- and
foreign antigens occurs without immune activation. In contrast, efficient
antigen-specific immune activation occurs upon encounter of DCs with
nonself-pathogens. Recognition of pathogens by DCs triggers specific receptors
such as TLRs that result in DC maturation and subsequently immune activation.
Here we discuss the concept that cross talk between TLRs and CLRs,
differentially expressed by subsets of DCs, accounts for the different pathways
to peripheral tolerance, such as deletion and suppression, and immune
Monocytes are circulating macrophages that can enter tissue spaces and
promote inflammation. Macrophages are found within the endothelium generally and
are concentrated in the lung, liver and spleen where they remove antigen and
immune complexes from the blood. Some tissues have resident macrophages such as
the Langerhan's cells in the skin. Killer T-cells recognize antigen presented on
MHC class I on all types of somatic cells. The purpose of the surveillance is to
detect, and respond to foreign antigens. Since most antigens are proteins and
foreign proteins arrive daily in the food ingested, I am interested in the
mechanisms by which food proteins activate immune cells and cause disease.
APCs can ingest foreign protein and process them into peptides in
proteasomes. Peptides are then transported into the endoplasmic reticulum to MHC
class I molecules for presentation. Houde et al, for example, showed that latex
beads labelled with fluorescent ovalbumin (egg white protein) were ingested and
fluorescence could be detected in the cytoplasm, indicating that proteins are
moved from outside into the cyoplasm for degradation by proteasomes. They showed
that phagosomes are a site of loading onto MHC class I molecules on the cell
surface, leading to T-cell stimulation.
Two major groups of lymphocytes are recognized as Thymus dependent or
T-lymphocytes; and Bursa dependent or B-lymphocytes. Adaptive immune responses
require B cells to provide antibody and T cells to provide cell-mediated
immunity. Cell surface receptors recognize antigens. B-lymphocytes learn make
antibodies to specific antigens. Although T and B cells share a common
progenitor, their development occurs in different locations in the body. B cells
develop in the bone marrow and mature in lymphoid tissue. T lymphocyte
progenitors leave the bone narrow and travel to the thymus where they mature.
The identity of a foreign molecule, microorganism or cell, is recognized by
an antigenic determinant, an amino acid sequence, usually contained in an intact
protein. Once an antigenic determinant is recognized, its sequence is remembered
by clones of antigen-specific B and T-memory cells which can activate other B
lymphocytes that make antibodies against the antigen. T memory cells are also
referred to a as helper T cells which are activated by the binding of a specific
antigen encountered in the past, a signal that initiates defense against
One of the growing complexities in immunology is the description of cell
surface receptors for a growing list of cytokines. Research reports are dense
with acronyms, abbreviations and codes that may deter even an experienced
reader. Some of these markers are described as CD followed by a number; CD122,
for example is a receptor for interleukin 2- . In addition some descriptions
emphasize the presence or absence of a well-studied receptor; CD122 + or -. CD
receptors may be associated with other surface molecules in complexes. For
example, natural killer T lymphocytes (NKT) have CD94-NKG2 complexes that bind
to major histocompatibility complex (MHC) class Ib, aka Qa-1, on the surface of
antigen presenting cells. CD8+ suppressor T cells regulate peripheral immune
The frequencies of blood lymphocyte subsets are monitored by flow cytometry
using monoclonal antibodies to identify subtypes: for example, OKT4 identifies
CD4+, T-helper cells and OKT8 identifies CD8+, T-suppressor cells.
Virus-specific CD8 and CD4 T lymphocytes play an important role in
controlling HIV replication; however CD4 and CD8 lymphocytes are infected by HIV
virus. Identifying and counting CD4 cells is a major tool in following patients
with AIDs taking antiretroviral medications.