2-Secondary immune deficiencies
Secondary immune deficiencies are much more common
than primary immune deficiencies).
Causes of secondary immune deficiency
Physiological
• Ageing
• Prematurity
• Pregnancy
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
T-CELL IMMUNODEFICIENCIES
Acquired immunodeficiency syndrome (AIDS)
By far the most common immunodeficiency worldwide is
that due to infection with the human immunodeficiency
virus (HIV), the cause of AIDS. Although the most
profound deficiency is in CD4 T-cells, B cells are also
affected to give a mixed pattern.
. Mechanisms of CD4 loss/dysfunction in HIV infection
1-Direct cytopathic effects of HIV
2-Lysis of infected cells by HIV-specific cytotoxic Tcells
The central and most characteristic is the progressive and
severe depletion of CD4+ 'helper' lymphocytes. As
described earlier,
these cells orchestrate the immune
response,
responding to antigen presented to them via
antigen-presenting cells in the context of class II MHC.
They (CD4)proliferate and release cytokines, particularly
1-IL-2. This leads to proliferation of other reactive T-cell
clones, including cytotoxic T cells, (which eradicate viral
infections),
2- gamma-interferon (which activates NK cells to
cytotoxicity) and macrophages (microbicidal activity
against intracellular pathogens). Loss of this single cell
type can therefore explain nearly all the immunological
abnormalities of AIDS
HYPERSENSITIVITY DISEASES
'is reactivity of an host to an agent on a second or
subsequent occasion'.
Hypersensitivity reactions include a number of
1-autoimmune and -2-allergic conditions
1-AUTOIMMUNE DISEASE
Autoimmunity can be defined as the presence of immune
responses against self-tissue
CHARACTERISED BY present of auto antibody and
auto reactive T cells
The spectrum of autoimmune disease
Type
Disease
A-Organ-specific
Immune response directed against localised antigens
Graves' disease
Hashimoto's thyroiditis
Addison's disease
Pernicious anaemia
Type 1 diabetes
Idiopathic thrombocytopenic purpura
Autoimmune haemolyticanaemia
Myasthenia gravis
Rheumatoid arthritis
Dermatomyositis
B-Multisystem
Immune response directed to widespread target antigens
Systemic sclerosis,
Mixed connective tissue disease
SLE
Physiology and pathology of autoimmunity
(PATHOPHYSIOLOGY)
1-Immunological tolerance
Failure of immune system distinguishes self from foreign
tissue,
. Here, T and B lymphocytes that recognize self antigens
are eliminated before they develop into fully immune
competent cells..
2-Factors predisposing to autoimmune disease
1-Both A- genetic and B-environmental factors
contribute.
. The most important genetic determinants of autoimmune
susceptibility are the HLA genes,
HLA associations in autoimmune disease
Disease HLA association Relative risk
Ankylosing spondylitis
B27
∼90:1
Type 1 diabetes DR3/DR4
∼20:1
Rheumatoid arthritis DR4
∼5:1
Graves' disease DR3
∼5:1
Myasthenia gravis
DR3
∼3:1
Several environmental factors can trigger autoimmunity
in genetically predisposed individuals. 1-infection, as
occurs in acute rheumatic fever following streptococcal
infection or reactive arthritis following bacterial infection.
A number of mechanisms have been responsible , such as
a-cross-reactivity between the infectious pathogen and
self determinants (molecular mimicry),
2-a side-effect of drug treatment. For example, the
metabolic products of the anaesthetic agent halothane
bind to liver enzymes, resulting in a structurally novel
protein. This is recognised as a new (foreign) antigen by
the immune system, and the autoantibodies and activated
T cells directed against it may cause hepatic necrosis.
Classification of autoimmune diseases
1-classified as organ-specific or multisystem
2-mechanism responsible for tissue damage. The Gell and Coombs
classification of hypersensitivity
Gell and Coombs classification of hypersensitivity
diseases
Type
Mechanism
Example of
disease in
response to
exogenous
agent
Example of
autoimmune
disease
Type I
Immediate
hypersensitivity
IgE-mediated
mast cell
degranulation
Allergic disease
None described
Type II
Antibody-
mediated
Binding of
cytotoxic IgG or
IgM antibodies to
antigens on cell
surface causes
cell killing
1-ABO blood
transfusion
reaction
2-Hyperacute
transplant
rejection
1-Autoimmune
haemolyticanaemia
2-Idiopathic
thrombocytopenic
purpura
3-Goodpasture's
disease
Type III
Immune
complex-
mediated
IgG or IgM
antibodies bind
soluble antigen to
form immune
complexes which
1-Serum
sickness
2-Farmer's lung
e.gSLE
trigger classical
complement
pathway
activation
Type IV
Delayed type
Activated T cells,
phagocytes and
NK cells
1-Acute cellular
transplant
rejection
2-Nickel
hypersensitivity
1-Type 1 diabetes
2-Hashimoto's
thyroiditis
Type I hypersensitivity is relevant in allergy but is not associated
with autoimmune disease.
In type II hypersensitivity, injury is localised to a single tissue or
organ.
Type III hypersensitivity is a generalised reaction resulting from
immune complex deposition in blood vessel walls, skin, joints and
glomeruli, where
they cause a chronic inflammatory response
.
gives rise to systemic diseases such as SLE.
In type IV hypersensitivity, activated T cells and macrophages
mediate phagocytosis and NK cell recruitment.
Investigations in autoimmunity
1-Autoantibodies
can be identified in the laboratory, and are useful in disease diagnosis
and monitoring.
-Rheumatoid factor
A rheumatoid factor is an antibody directed against the common (Fc)
region of human IgG. Rheumatoid factors may be of any
immunoglobulin class but IgM is most commonly tested
CONDITIONS ASSOCIATED WITH A POSITIVE RHEUMATOID
FACTOR
Disease Frequency (%)
Rheumatoid arthritis with extra-articular manifestations 100 %
Rheumatoid arthritis (overall) 75%
Sjögren's syndrome 90 %
Primary biliary cirrhosis 50 %
Subacute bacterial endocarditis 40 %
SLE 30 %
Tuberculosis 15%
Elderly (> 65 years) 20
. Only 50% of patients with rheumatoid arthritis are positive for
rheumatoid factor
at the time of diagnosis
; a further 25% will become
seropositive
in the first 2 years of disease
(. Thus this test is
insufficiently sensitive
to rule out rheumatoid arthritis. In addition,
rheumatoid factor
has low specificity
for rheumatoid arthritis, being
associated with a wide variety of autoimmune and non-autoimmune
conditions, and a common finding in the elderly (). The major indication
for rheumatoid factor testing is
to evaluate prognosis
in rheumatoid
arthritis, as it is associated with more severe erosive disease and extra-
articular disease manifestations such as nodules, vasculitis and Felty's
syndrome.
Anti-CCP antibody
Antibodies to cyclic citrullinated peptide (anti-CCP antibodies) bind to
peptides in which the amino acid arginine has been converted to
citrulline by peptidylarginine deiminase, an enzyme abundant in the
inflamed synovium.
It is a more specific test for rheumatoid arthritis
than rheumatoid factor and a
better predictor of an aggressive disease
course. In patients with undifferentiated arthritis, anti-CCP antibodies
may predict those who are likely to develop rheumatoid arthritis.
Antinuclear antibodies
CONDITIONS ASSOCIATED WITH A POSITIVE ANTINUCLEAR
ANTIBODY
SLE
∼100%
Scleroderma 60-80%
Sjögren's syndrome 40-70%
Dermatomyositis or polymyositis 30-80%
Mixed connective tissue disease 100%
N.B. 5% of healthy individuals have an ANA titre > 1:80.
Antinuclear antibodies (ANA) are a group of antibodies which bind to
components of the nucleus.
The major indication for ANA testing is in the diagnosis of SLE, where
it has a very high sensitivity (almost 100%), and a negative ANA test
virtually excludes the diagnosis. However, the specificity is low (, and
ANA may be present in low titre in healthy individuals.
Anti-DNA antibodies
Anti-DNA antibodies bind to double-stranded DNA and are highly
specific for SLE (95%). They occur in up to 60% of SLE patients at
some time in their disease course.
Antiphospholipid antibodies
Antiphospholipid antibodies are associated with the development of
venous and arterial thrombosis and recurrent fetal loss
. This may occur
in isolation (primary antiphospholipid syndrome), or as a complication
of SLE (secondary antiphospholipid syndrome).
, but the most commonly measured are
anticardiolipin antibodies and lupus anticoagulant.
2-Measures of complement activation
Measuring complement useful in the evaluation of immune complex-
mediated diseases(type III). Classical complement pathway activation
leads to a decrease in circulating C4, and decreased C3 levels. Serial
measurement of C3 and C4 is a useful surrogate measure of immune
complex formation.
3-C-reactive protein (CRP)
4-Erythrocyte sedimentation rate (ESR)
In allergies
, the immune system reacts to an outside substance that it
normally would ignore.
With autoimmune disorders
, the immune system reacts to normal
body tissues that it would normally ignore.
Symptoms of an autoimmune disease vary based
on the disease
and
location of the abnormal immune response
.