Immune regulation

.
There are two principal types of antigen recognition
.receptors: antibodies and T-cell receptors (TCRs)
Antibodies, or immunoglobulins, are expressed as cell
surface receptors on B cells and presenting the antigen to
helper T cells, ((in antigen presentation
Antigen is any substance capable of generating an immune
,response
B cell receptor recognized unprocessed ⚫
antigen(protein, lipid , polysucrided , neuclic acid)
T cell receptor recognize the processed peptide ⚫
presented by MHC molecule on the surface of other
cell
T cell receptor bind to peptide\MHC complex ⚫
In primary immune respons when Ag first introduce in to body
there is lag phase of several days during which no Ab .detected
.,then several day later(7-10 days)IgM Ab appear
IN secondary immune respons A group of B.cell called
memory cell ,enhance immune response to previously
encountered Ag (the lag phase IS decrease)
the first antibody to be produced is IgM, which appears in the ,
serum after 5-10 days., other antibody classes (IgG, IgA and IgE)
are produced 3-7 days later. If, some time later, a memory B cell
is re-exposed to antigen, the lag time between antigen exposure
and the production of antibody is decreased (to 2-3 days
.
⚫ HUMAN LEUCOCYTE ANTIGENS
Antigen presentation ⚫
The immune system has the ability to . ⚫
recognize between 'self' and 'non-self'
antigens. This process is facilitated by a
recognition system called the major
histocompatibility complex (MHC)
which dictates the way that antigen is
recognized as foreign. In man, the
products of MHC are termed human
.leucocyte antigens (HLA)
The HLA system
is cluster of genes is located on the short arm of ⚫
chromosome 6. The system comprises six genetic loci -
HLA-A, -B, -C, -D, -DR and –DQ. The gene encodes the
HLA molecules(cell surface antigen presenting
proteins)which are distributed throughout the body tissues
and it is through differences in HLA that cells are
.classified as self or non-self
Why; individual differences in susceptibility to a variety ⚫
.of autoimmune, inflammatory, and infectious disorders
HLA genes display a remarkably high degree of genetic ⚫
variation among individuals in the population, and this
variability is largely responsible for individual differences
.in immune responsiveness
 The possibility of two different individuals having
the same combination of HLA molecules is very
remote.. The HLA genes code for cell-surface
glycoproteins that extend from the plasma
membrane to the cytoplasm and are known as class I
and class II molecules. These glycoproteins consist of
two chains of unequal size (α and β chains). The
chains form a groove in which an antigenic peptide
sits ready for presentation to T cells.
Class I HLA molecules

⚫ Class I (HLA-A, -B and -C) are expressed on all cell

types except erythrocytes and trophoblasts..
⚫ Class I molecules interact with CD8 T cells during
antigen presentation and therefore are involved in
driving mainly cytotoxic reactions.
.
 Class II HLA molecules

⚫ Class II (HLA-D and -DR, D-related) are expressed

only on professional antigen-presenting cells (B cells,
monocytes/macrophages, Langerhans' cells, dendritic
cells) and activated T cells. Class II antigens link with
CD4 molecules during antigen presentation and the
reaction induced by cells bearing this molecule is
therefore of the helper type.
Components of the immune
.response
⚫ . T helper cells respond to protein antigens, but they
cannot recognise these in their native form. Instead, intact
protein must be processed into component peptides which
can bind to the cell surface HLA . This process is known
as antigen processing and presentation, and it is the
peptide/HLA complex which is recognised by individual T
cells.
⚫ Antigen is presented to T-helper cells (Th cells) by an antigen-presenting cell. Th
cells secrete lymphokines(cytokine), which
⚫ 1-activate cytotoxic T cells (Tc cells) that are involved in antiviral and anti-tumour
activity.
⚫ 2-activate NK cells and macrophage, which are involved in antitumor activity.
mediate tissue damage and trigger inflammatory responses in which eosinophils
predominate
⚫ 3-induction of antibody responses by B cells

⚫ • Helper T cells are unable to destroy pathogens or cells directly, but through
cytokine production are able to activate macrophages to kill organisms within
them and further activate cytotoxic T cells and NK cells.
When a foreign pathogen enters the body, ⚫
specific cells called antigen-presenting cells (APCs)
engulf the pathogen through a process
called phagocytosis. Proteins from the pathogen are
digested into small pieces (peptides) and loaded onto HLA
antigens (to be specific, MHC class II). the HLA system
brings fragments of the virus to the surface of the cell
They are then displayed by the antigen-presenting ⚫
cells to CD4+ helper T cells,[3] which then produce a
variety of effects to eliminate the pathogen
HLAs have other roles. They are important in disease ⚫
defense. They are the major cause of organ transplant
rejections. They may protect against or fail to protect (if
down-regulated by an infection) against
cancers.[1] Mutations in HLA may be linked
to autoimmune disease (examples: type I diabetes, coeliac
.disease)
Cytotoxic Tcell
Cells infected with virus bind viral protein fragment on to ⚫
the HLA molecule and present them on their surface
cytotoxic T cell recognize the HLA and protein-2 ⚫
fragment through T cell receptor and attack the infected
cells
Natural killer (NK) cells are effector lymphocytes of ⚫
the innate immune system that control several types
of tumors and microbial infections by limiting their
spread and subsequent tissue damage

promote antitumor immunotherapy and control ⚫

.inflammatory and autoimmune disorders
By producing cytokine NK cells boost the maturation ⚫
and activation of DCs, macrophages and T cells
T lymphocytes are classified into
⚫ 1-Helper/inducer cells

⚫ Bear CD4 cell surface molecule ( cytokine-secreting

cells), making up about 75% of peripheral blood T
cells) and the ability to recognize antigen only when
the Ag expressed with HLA class II on
antigen-presenting cells.
⚫ 2-Cytotoxic/suppressor cells
⚫ Bear CD8cell surface molecule (mainly cytotoxic
suppressor cells) , which account for the remainder.able
to recognize antigen only when presented with HLA class I
molecules
⚫ These cell types are indistinguishable morphologically,
but can be separated by the presence of cell-surface
molecules CD(specific target molecule on a cell that is
recognized by one or more antibodies).
Some diseases show a close •
association with HLA type. HLA -
associations with disease
A1, B8, DR3 Polymyositis and
dermatomyositis
A3, B14 Hereditaryhaemochromatosis

A28 Schizophrenia
B5 Behçet's syndrome
Polycystic kidney disease
Ulcerative colitis
B8, DR3, DR7, DQ2 Coeliac disease
B18 Hodgkin's disease
B27 Acute anterior uveitis
Ankylosing spondylitis
Psoriatic arthropathy
Reiter's syndrome
Juvenile arthritis
many individuals who carry these risk alleles do not ⚫
contract the disease. Conversely, a substantial number of
individuals with the disease do not carry the known HLA
risk-conferring alleles. Thus, in a practical sense, HLA
typing alone is not very useful in a clinical setting for most
.diagnostic purposes
This pattern of association, in which HLA alleles confer a state of risk or ⚫
susceptibility to disease, implies that other factors must be involved for a
disease to actually manifest. In general, these other factors can include
,other -genes-1 ⚫
,environmental factors-2 ⚫
and3- nongenetic factors such as“epigenetic” events that may occur at any ⚫
.time during development
These factors explain why concordance rates for many autoimmune . ⚫
disorders in monozygotic twins are only in the 30% range, even though
these diseases all exhibit significant genetic associations with particular
HLA alleles and have a strong genetic component. The genetic
predisposition conferred by the MHC is only part of the overall genetic
contribution to most autoimmune disorders, and the MHC component
.varies in importance, depending on the particular disease
IMMUNE DEFICIENCY
⚫ Immune deficiency may arise through
⚫ 1-primary ,intrinsic defects in immune function,
⚫ 2- secondary causes (most comon)
⚫ The consequences(complications) of deficiencies of the
immune system include
1. recurrent infections,
2. autoimmunity and
3. susceptibility to malignancy.
Failure of self-tolerance results in immune responses against ⚫
self-antigens. Such reactions are called autoimmunity and may
give rise to chronic inflammatory autoimmune disease
Peripheral tolerance of B cells is maintained through the ⚫
absence of T-cell help. B cells require signals from T cells to
differentiate into effector cells. B lymphocytes that recognize
self-antigens in the periphery in the absence of T-cell help are
rendered anergic or are unable to enter lymphoid follicles,
where they could receive T-cell help, effectively excluding
.them from immune responses
. Presenting problems in immune deficiency is
Recurrent infections
. Frequent, severe infections or infections caused
by unusual organisms or at unusual sites are the
most useful indicator. If an immune deficiency is
suspected but has not yet been formally
characterised, patients should not receive live
vaccines because of the risk of vaccine-induced
disease.
Warning signs of immune
deficiency
• ≥ 8 ear infections within 1 year
• ≥ 2 serious sinus infections within 1 year
• ≥ 2 months on antibiotics with little effect
• ≥ 2 pneumonias within 1 year
• Failure of an infant to gain weight or grow normally
• Recurrent deep skin or organ abscesses
• Persistent thrush in mouth or elsewhere on skin after infancy
• Need for intravenous antibiotics to clear infections
• ≥ 2 deep-seated infections such as sepsis, meningitis or cellulitis
• A family history of primary immune deficiency
1-PRIMARY IMMUMEDEFICIENCY
⚫ A-Primary deficiency in innate immune system
Primary phagocyte deficiencies-1 ⚫
Leucocyte adhesion deficiencies-2 ⚫
These are disorders of phagocyte migration, when failure to ⚫
express adhesion molecules on vascular endothelium results in
.the inability of phagocytes to exit the blood stream
Defects in cytokines and cytokine receptors-3 ⚫
Defects of cytokines such as IFN-γ, IL-12 or their receptors ⚫
also result in failure of intracellular killing, and individuals are
particularly susceptible to mycobacterial infections..Q WHY
INTRA
Complement pathway deficiencies-4 ⚫
Genetic deficiencies of almost all the complement pathway ⚫
.proteins have been described
Clinical .Features. ⚫
recurrent infection with encapsulated bacteria, particularly-1 ⚫
.Neisseria species
a high prevalence of autoimmune disease, particularly -2 ⚫
.systemic lupus erythematosus
Deficiency of the regulatory protein C1 esterase inhibitor is-3 ⚫
not associated with recurrent infections but causes recurrent
.angioedema
B-Primary deficiencies of the
adaptive immune system
Primary T-lymphocyte deficiencies-1 ⚫
These are characterised by recurrent viral, protozoal and ⚫
fungal infections . In addition, many T-cell deficiencies
are associated with defective antibody production because
.of the importance of T cells in providing help for B cells
Combined B- and T-lymphocyte immune-2 ⚫
deficiencies
causes recurrent bacterial, fungal and viral ⚫
infections soon after birth. Bone marrow
transplantation is the only current treatment
option, although specific gene therapy is under
.investigation
Primary antibody deficiencies-3
,characterisedby recurrent bacterial infections ⚫
A-SELECTIVE IMMUNOGLOBULIN A DEFICIENCY ⚫
Selective IgA deficiency is the most common primary ⚫
immunodeficiency disorder and is characterized by serum ⚫
;IgA levels 15 mg/dL with normal levels of IgG and IgM
.its prevalence is about 1:500 individuals ⚫
⚫ Clinical .Features
⚫ 1-Most persons are asymptomatic because of
compensatory increases in secreted IgG and IgM.
⚫ 2-frequent and recurrent infections, such as sinusitis,
otitis, and bronchitis.
⚫ 3-Individuals with selective IgA deficiency may have high
titers of anti-IgA antibodies and are at risk for
anaphylactic reactions following exposure to IgA through
infusions of plasma (or blood transfusions). These anti-IgA
antibodies develop in the absence of prior exposure to
human plasma or blood, possibly due to cross reactivity to
bovine IgA in cow’s milk or prior sensitization to maternal
IgA in breast milk.
⚫ TREATMENT

⚫ Some cases of IgA deficiency may spontaneously remit.

Treatment with commercial immune globulin is
ineffective, since IgA and IgM are present only in trace
quantitiesin these preparations
B-Common variable immune deficiency (CVID)
#.intrinsic B cell defects that prevent terminal maturation
into antibody-secreting plasma cells.
#The absolute B cell count in the peripheral blood is
normal
#It is characterized by low serum IgG levels but over time
all antibody classes (IgG, IgA, and IgM)may be affected .
and failure to make antibody responses to exogenous
pathogens.
⚫ CLINICAL FEATURES
⚫ 1- an increased incidence of recurrent infections,
⚫ 2-autoimmune phenomena, Paradoxically, antibody-mediated
autoimmune diseases such as idiopathic thrombocytopenic
purpura and autoimmune haemolytic anaemia are common
autoimmune endocrinopathies , seronegative rheumatic
disease, and gastrointestinal disorders are also commonly seen
⚫ 3-neoplastic diseases There is an increased propensity for the
development of B cell neoplasms (increaserisk of lymphoma),
gastric carcinomas, and skin cancers
Management

All patients with antibody deficiencies require aggressive-1 ⚫

treatment of infections and prophylactic antibiotics may be
.indicated
The mainstay of treatment is immunoglobulin replacement -2 ⚫
(intravenous immunoglobulin, IV IgG contains IgG antibodies
to a wide variety of common organisms. IVI gG is usually
administered every 3-4 weeks with the aim of maintaining
trough IgG levels within the normal adult range. Treatment
.may be self-administered and is life-long
With the exception of selective IgA deficiency, immunisation ⚫
is generally not effective because of the defect in IgG antibody
production. As with all primary immune deficiencies, live
.vaccines should be avoided
Secondary immune deficiencies-2
Physiological ⚫
Ageing , Pregnancy Prematurity • ⚫
Infection • • ⚫
HIV ,Measles ,Mycobacterial infection • ⚫
Iatrogenic ⚫
Immunosuppressive therapy Antineoplastic agents • ⚫
Corticosteroids ,Stem cell transplantation ,Radiation injury • ⚫
Anti-epileptic agents •
Malignancy ⚫
B-cell malignancies including leukaemia, lymphoma and • ⚫
myeloma Solid tumours Thymoma
⚫
Biochemical and nutritional disorders ⚫
Malnutrition • ⚫
Renal insufficiency/dialysis • ⚫
Diabetes mellitus • ⚫
Specific mineral deficiencies, e.g. iron, zinc • ⚫
Other conditions ⚫
Burns • ⚫
Asplenia/hyposplenism • ⚫