The immune system
The primary lymphoid organs include the bone marrow and the
thymus. They create special immune system cells called lymphocytes.Secondary lymphoid organs include the lymph nodes, the spleen,
the tonsils and mucosally associated lymphoid tissue (MALT). MALT is
present in the gut, pharynx, bronchi, breast tissue, genitourinary
system and the salivary and lacrimal glands. Lymphoid organs appear
early in gestation. The thymus appears first, producing cells at 8 weeks
which become immunocompetent at 11 weeks. The total population of
lymphoid tissue is completed by 16 weeks of gestation. The bone marrow
gives rise to the cells of the blood (the haemopoietic system). Some of
these cells are involved in the recognition of antigen and mounting of
an immune response (lymphocytes), while others are involved in
elimination (e.g. macrophages and granulocytes). The thymus is derived
from the third and fourth pharyngeal pouches, thus giving it an
epithelial framework. It becomes populated by T lymphoblasts produced in
the bone marrow, matures in the thymus generating large numbers of
specific T lymphocytes. Thymus output is essential during early life to
establish immune competence and homeostasis but is dispensable
thereafter [1, 7]. The tissue cells of the mononuclear
phagocyte system are derived from blood monocytes and constitute
approximately 5% of the total number of leucocytes. They are large and
possess a bean-shaped nucleus. They have abundant cytoplasm containing
lysosomes, rough endoplasmic reticulum and other organelles, rendering
them capable of division and longevity. Immunoglobulin (IgG, IgE) and
complement (C3, C5) receptors on their cell surface allow them to bind
immune complexes. They can be divided depending on their function into
antigen presenting cells, macrophages, multinucleate giant cells and
sinus-lining histiocytes. Within the immune system the antigen
presenting cells (APC) are of particular importance. They are involved
in interactions between T cells and B cells as a result of their ability
to bind antigen-antibody complexes on their surface. The presentation of
partially degraded antigen-antibody complexes or free antigen to T and B
lymphocytes is important in humoral immunity. Tissue histiocytes are
related cells, pinocytotic and facultative phagocytes found in most
organs, particularly lining sinusoidal spaces in the spleen, lymph node
and liver Their engulfment and digestion of cell debris and foreign
material is important in non-specific immunity [8-10].
Lymphocytes are distributed in all organs , tissues, interstitial
fluids except the brain. Lymphocytes account for up to 45% of the
circulating blood leucocytes. They are divided into T lymphocytes (
thymus- derived T cells)-70% of total lymphocytes, B lymphocytes cells
derived from the bursa of Fabricius (in birds)-20% of total, and ‘Null’
Cells (10% of total). T cells are mainly involved with cell mediated
immunity whilst B cells are involved in humoral immunity. Immunological
memory is carried by long-living T and B cells. The T lymphocytes
migrate from the bone marrow to the thymus where they are processed by
the thymic epithelial cell hormone, which transforms them into
immunocompetent cells. They are activated to form ‘blast’ cells by
specific antigens and non-specific mitogens such asphytohaemoglutinin (PHA). The activation involves macrophages
(antigen- presenting cells), which process and present the antigen to
the lymphocytes. T lymphocytes live for months or years and are divided
into subsets depending on their role in the immune response, either
regulating antibody production through the secretion of interleukins ( T
helper (TH ) or T suppressor cells (Ts), directly
cytotoxic (T cytotoxic (Tc) or taking part in delayed hypersensitivity
reactions (T delayed hypersensitivity cells (TD)).
Following the T cell interaction with antigen in association with the
HLA glycoprotein (the T cell receptor complex), non-specific lymphokines
and interleukins are released which amplify the immunological response.
For example many bacteria and protozoa can survive within phagocytic
cells (macrophages).These cells may be activated by
macrophage-activation factor (MAF) from specifically sensitized T
lymphocytes, causing release of intracellular lysosomal enzymes and
destruction of the infecting agents. T lymphocytes are the most potent
mediators of adaptive anti-tumour immune response. The T cell mediated
immunity can be transferred by giving T cells to a genetically
compatible individual. In addition, the transfer factor, a soluble
extract of T cells, can transfer some T cell functions which is applied
in immunotherapy for cancer or infection [1, 2]. It is important to
note that T cells have proteins on them that turn on an immune response
for an example when an infection is present, and other proteins that
turn it off. These are called checkpoint proteins because if T
cells are active for too long, or react to things they shouldn’t , they
can start to destroy healthy cells and tissues [11]. B lymphocytes
are derived from the bone marrow , are thought to be processed in the
fetal liver and spleen and the adult bone marrow in mammals, and live
for days or weeks. Although B cells and T cells are fundamentally
similar, they differ in their surface receptors and markers (table 1).
They use antigen receptors to recognize foreign material, and both
undergo a first stage of proliferation in one organ while simultaneously
inducing specificity through rearrangement of their antigen-receptor
genes. They then undergo a second antigen- driven proliferation at
another site, usually a secondary lymphoid organ. Finally, they produce
a functional cell, B cells giving rise to immunoglobulin-secreting
plasma cells and T cells to functional cytotoxic T cells and helper T
cells. Although antibody synthesis is inhibited by Ts cells,
TH and B cell interaction is essential for an optimal
humoral response to most antigens [1, 2]. The human immunodeficiency
virus(HIV) is an RNA retrovirus that infects human T lymphocytes. The
suppressed cellular immunity manifesting as the acquired immune
deficiency syndrome (AIDS) allows the development of malignancies
(Kaposi’s sarcoma, lymphoma) and opportunistic infections
(pneumocystis jiroveci pneumonia, cryptosporidium,
cytomegalovirus (CMV), herpes simplex (SV), disseminated
tuberculosis and candida 5-10 years later [12]. B cell and T
cell hyperplasia are the basis of lymphomagenesis with T- cell lymphomas
being clinico-pathologically more severe than B-cell lymphomas. The
combination of recurrent plasmodium (P. falciparum) malaria and
Epstein-Barr virus (EBV) infection very early in childhood cause B cell
hyperplasia which is an essential component of Burkitt’s
lymphomagenesis. This EBV-associated lymphoma was one of the first
tumours shown to have chromosomal translocation ( chromosome 14) that
activates an oncogene (c-MYC) . The transformation of these cells
compromises host defence and evolves mechanisms to escape immune
surveillance. Thus, Burkitt’s lymphoma patients do not usually exhibit
the B- symptoms ( fever, night sweats, and weight loss ) [13, 14] .
HIV-associated Burkitt’s lymphoma is associated with EBV in
approximately 40% of cases [13]. T cell hyperplasia is mainly
caused by infection with the Human T- lymphotropic retrovirus (HTLV-1)
virus which may give rise to adult T-cell lymphoma/ leukaemia [15].
The ‘Null’ cells originate from the bone marrow but are lymphocytes that
do not possess the phenotype surface markers of either T or B cells.
Some may be identical to ‘killer’ (k) cells, which have cytotoxic
properties against target cells coated with antibody, and some may be
‘natural killer’ (NK) cells, which are thought to lyse certain tumour
cells [1, 16 ].
Polymorphonuclear granulocytes (neutrophils) originate from bone
marrow derived myeloid cells, and circulate in the bloodstream.
Neutrophils live for 6-20 h and constitute approximately 60% of the
total number of leucocytes. They bear surface receptors for IgA, IgG and
complement components. Neutrophils play a primary role in non-specific
immunity by engulfing and digesting microorganisms, and their absence
usually proves fatal [17].. Mast cells are
present in the skin and mucosal surfaces, and basophils circulate
in the blood, where they constitute 0.5 to 2% of the circulating
leucocytes. Although direct proof of common origin is lacking both mast
cells and basophils are involved in type 1 immediate hypersensitivity
reactions, when they release inflammatory mediators following allergen
binding to IgE on their surface . They also bear receptors for
complement components. Circulating basophils show an increase in
allergic disease states and are seen in secretions of patients with
allergic rhinitis. Eosinophil granulocytes originate from myeloid
precursors in the bone marrow and circulate in the bloodstream, where
they constitute 2-5% of the total number of leucocytes, although they
may account for up to 20% in individuals with immediate sensitivity
diseases or helminth infestation. They live for 6-20 h and bear
receptors for IgG and complement components. Thus their primary
activities are to engulf and digest immune-complexes important against
helminth infection, and the release of enzymes that are able to
inactivate biologically-active substances such as histamine in type I
hypersensitivity reactions [18].