Immune deficiency diseases

may be caused by :
1. inherited defects affecting immune system
development,
2. or they may result from secondary effects of
other diseases (e.g., infection, malnutrition,
aging, immunosuppression, autoimmunity,
or chemotherapy).
Clinically
increased susceptibility to infections
 as well as to certain forms of cancer.
The type of infections in a given patient
depends largely on the component of the
immune system that is affected.
Patients with defects in Ig, complement, or
phagocytic cells typically suffer from recurrent
infections with pyogenic bacteria
 whereas those with defects in cell-mediated
immunity are prone to infections caused by
viruses, fungi, and intracellular bacteria.
Primary Immune
Deficiencies
Most primary immune deficiency diseases are
genetically determined and affect either:
1. adaptive immunity (i.e., humoral or cellular)
or
2.innate host defense mechanisms, including
complement proteins and cells such as
phagocytes and NK cells.
Defects in adaptive immunity are often
subclassified on the basis of the primary
component involved (i.e., B cells or T
cells, or both)
Most primary immune deficiencies
come to attention early in life (between
6 months and 2 years of age), usually
because the affected infants are
susceptible to recurrent infections
X-Linked
Agammaglobulinemia (XLA,
Bruton Disease)
It is characterized by the failure of pre-B cells to
differentiate into B cells;
there is a resultant absence of gamma globulin in
the blood
XLA does not become apparent until
approximately 6 months of age, when maternal
immunoglobulins are depleted.
recurrent bacterial infections such as acute and
chronic pharyngitis, sinusitis, otitis media,
bronchitis, and pneumonia suggest an underlying
immune defect
Because antibodies are important for
neutralizing viruses, these patients are also
susceptible to certain viral infections,
especially those caused by enteroviruses.
Similarly, Giardia lamblia, an intestinal
protozoan usually neutralized by secreted IgA,
cannot be efficiently cleared and causes
persistent infections
Isolated IgA Deficiency
IgA is the major Ig in mucosal secretions and is
thus involved in airway and gastrointestinal
defense. Although most individuals with this
condition are asymptomatic, weakened mucosal
defenses predispose patients to recurrent
sinopulmonary infections and diarrhea. There is
also a significant (but unexplained) association
with autoimmune diseases.
IgM and IgG subclasses of antibodies are
present in normal or even supranormal levels
Thymic Hypoplasia:
DiGeorge Syndrome
DiGeorge syndrome results from a congenital
defect in thymic development with deficient T-
cell maturation. T cells are absent in the lymph
nodes, spleen, and peripheral blood, and
infants with this defect are extremely
vulnerable to viral, fungal, and protozoal
infections. Patients are also susceptible to
infection with intracellular bacteria, because of
defective T-cell-mediated immunity. B cells and
serum immunoglobulins are generally
unaffected.
The disorder is a consequence of a
developmental malformation affecting the
third and fourth pharyngeal pouches-
structures that give rise to the thymus,
parathyroid glands, and portions of the face
and aortic arch. Thus, in addition to the
thymic and T-cell defects, there may be
parathyroid gland hypoplasia resulting in
hypocalcemic tetany, as well as additional
midline developmental abnormalities
Severe Combined
Immunodeficiency
Severe combined immunodeficiency (SCID)
represents a constellation of genetically
distinct syndromes with the common feature of
defects in both humoral and cell-mediated
immune responses. Affected infants are
susceptible to severe recurrent infections by a
wide array of pathogens, including bacteria,
viruses, fungi, and protozoans; opportunistic
infections by Candida, Pneumocystis, CMV, and
Pseudomonas also cause serious (and
occasionally lethal) disease.
the thymus is hypoplastic. Lymph nodes and
lymphoid tissues (e.g., in the tonsils, gut, and
appendix) are atrophic and lack B-cell
germinal centers as well as paracortical T
cells. Affected patients may have marked
lymphopenia, with both T- and B-cell
deficiency; others may have increased
numbers of immature T cells and/or large
numbers of B cells that are nonfunctional
because of a lack of T-cell help
Genetic Deficiencies of
Components of Innate
Immunity
 Complement Proteins
 complement components play important roles in inflammatory and
immunologic responses. Consequently, hereditary deficiency of
complement components, especially C3 (critical for both the classical and
alternative pathways), results in an increased susceptibility to infection with
pyogenic bacteria. Inherited deficiencies of C1q, C2, and C4 do not make
individuals susceptible to infections, but they do increase the risk of
immune complex-mediated disease (e.g., SLE), possibly by impairing the
clearance of apoptotic cells or of antigen-antibody complexes from the
circulation. Deficiencies of the late components of the classical complement
pathway (C5-C8) result in recurrent infections by Neisseria (gonococci,
meningococci) but, curiously, not by other microbes. Lack of the regulatory
protein C1 inhibitor allows unfettered C1 activation, with the generation of
down-stream vasoactive complement mediators; the result is hereditary
angioedema, characterized by recurrent episodes of localized edema
affecting the skin and/or mucous membranes.
 0 Phagocytes Body_ID: HC005087 Several congenital defects in
phagocytes are known. These include defects in the phagocyte oxidase
enzyme, the cause of chronic granulomatous disease, and defects in
integrins and selectin ligands, causing the leukocyte adhesion deficiencies.
These disorders were described in Chapter 2.
Secondary Immune
Deficiencies
Immune deficiencies secondary to other
diseases or therapies are much more common
than the primary (inherited) disorders.
Secondary immune deficiencies may be
encountered in patients with malnutrition,
infection, cancer, renal disease, or sarcoidosis.
However, the most common cases of immune
deficiency are therapy-induced suppression of
the bone marrow and of lymphocyte function
AIDS
• Acquired immune deficiency syndrome
secondary to infection with human
immunodeficiency virus HIV.
Characterized by :
1. Marked suppression in T-lymphocyte.
2. Secondary neoplasm.
3. Opportunistic infections.
4. Neurologic disease.
Modes of transmission
1. Sexual contact.
2. Parental inoculation.
3. Passage from the infected mother to fetus.
Virus structure
Retrovirus.
Lipid envelop derived from infected host
membrane.
Two viral gp120,gp41 & the former important
in binding to CD4 lymphocyte.
Pathogenesis
 Binding 0f the virus to target cells (CD4 LC,
lower level of monocyte & macrophage) &
virus internalized.
 Reverse transcription & viral DNA integrated
to host genome.
 Virus replications depend on T-cell
activation.
 Greater proportion of CD4 (+HIV) in LN
mostly in the latent phase.
 Infected monocyte & macrophage refractory
to cytopathic effect of the virus act as:
 reservoirs for HIV
 Vehicles for transport (CNS)
 These cells continuously infect T-cells as
they pass through LN.
 Continuous depletion T-cells lead to
immunodeficiency.
 Infected monocyte & macrophage refractory
to cytopathic effect of the virus act as:
 reservoirs for HIV
 Vehicles for transport (CNS)
 These cells continuously infect T-cells as
they pass through LN.
 Continuous depletion T-cells lead to
immunodeficiency.
Abnormalities of the
immune system
1. Lymphopenia
2. Decreased T-cell function.
• Opportunistic infections
• Neoplasm
3. Abnormal B-cell activation
4. Altered monocyte & macrophage function
• Decreased chemotaxis
• Diminished ability to present Ag to T-cell
History of HIV infection
1. Acute phase
• Transient viremia, seeding of lymphoid
tissue temporary fall in CD4-Tcells.
• Followed by seroconversion & control of viral
replication by CD8 antiviral cells.
• Acute illness sore throat, mylagia, clinical
recovery & near normal T-cells occur in 6-12
wk.
2. Chronic phase
Clinical latency
Low level of viral replication mainly in LN
Slow decrease in in CD4-Tcells.
Patient develop generalized LN enlargement.
7-10 years.
3. Crisis phase
Sharp decline in in CD4-Tcells.
Weight loss.
Diarrhea.
Opportunistic infections
Secondary neoplasm.
Clinical features of AIDS
1. Variety of opportunistic infections due to
defect in CMI .(pneumocyctis carini )occur in
50% of patients.
2. Wide spectrum of pyogenic infections. Due
to defect in humeral immunity.
3. Malignant neoplasm. Kaposi sarcoma 25%
more in homosexual. NHL 60 fold more than
general populations.
4. Neurological involovment 30%-50%