Download Immunodeficiency - quantitative or qualitative defects of immune

TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY,AND CLINICAL ASPECTS OF THE
IMMUNODEFICIENCY DISORDERS
Immunodeficiency - quantitative or qualitative defects of immune system
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may involve the cells and components of:
- natural defense system ( e.g. Defect of phagocytosis, complement mediated defense)
- acquired immunity involving T- and B- cells
• associated with an increase susceptibility of infection and lymphoproliferative disease
• PRIMARY – congenital, mostly genetic deficiencies of one or more components of immune
system
• SECONDARY – numerous acquired deficiencies of one and more components of immune system
caused by infection, malnutrition, drugs, irradiation, cancer or autoimmunity.
• B cell deficiencies
T- & B-cell deficiencies
• X-linked agammmaglobulinemia ( Bruton)
Hyper IgM syndrome
• Common variable immunodeficiency
DiGeorge syndrome
• Isolated IgA deficiency
Severe combined immunodeficiency
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY,AND CLINICAL ASPECTS OF THE
IMMUNODEFICIENCY DISORDERS
• X- linked agammaglobulinemia – Bruton type – is a sex linked recessive disease whose
pathogenesis involves the failure of pre-B cells to differentiate into mature B cells. Failure to
assemble complete immunoglobulin molecules is due to a mutation in btk (Brtuon tyrosinase kinase)
gene located on X q21.2-22 chromosome.
Maternally derived IgG protects the newborn for few months before affected infants begin to
develop sinopulmonary disease associated with Streptococcus pneumoniae, Haemophilus influenzae
and Staphylococcus aureus.
Since cell-mediated immunity is intact there is an effective host defense against most viruses and
fungi
• Common variable immunodeficiency – onset in late childhood of hypogammaglobulinemia and
recurrent infections. Boys and girls are affected equally. High frequency of malignancies – gastric
cancer, lymphoma – later in life.
• Isolated IgA deficiency – the most common hereditary immunodeficiency is due to an intrinsic
defect in the differentiation of B cells committed to synthesizing IgA or to a defect in T cells
that prevents B cells from synthesizing IgA.
Because IgA is the major immunoglobulin found in mucosal secretions ( respiratory, GI tract), IgA
immunodeficiency is characterized by recurrent sinusitis, pulmonary and urinary infections and
recurrent diarrhea.
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY,AND CLINICAL ASPECTS OF
THE IMMUNODEFICIENCY DISORDERS
• X- linked hyper IgM syndrome – persons have high titers of IgM and IgD but low level of
IgG, IgA and IgE antibodies, indicating defect in isotype switching.
• primary defect in CD4+ T- cells
• caused by mutation of X-chromosome gene coding Cd40L
Patients suffer from pyogenic infections and are susceptible to infection with
Pneumocystis carinii.
• DiGeorge syndrome – is failure of third and fourth pouches to develop due to deletion of
chromosome 21q11, with subsequent absence of all four parathyroid glands and thymus. Part of
CATCH 22 syndrome : Cardiac abnormalities, T cell deficit, Cleft plate , Hypocalcemia.
• Severe combined immunodeficiency – SCID
X-chromosome linked – boys are typically affected
Both humoral and cellular immunity responses are affected
Susceptibility to severe, recurrent fungal, viral and bacterial infections
• Wiskot-Aldrich syndrome – is sex linked recessive disease with triad of thrombocytopenia,
eczema and recurrent sinopulmonary infections complicate by an increased risk for
development of malignant lymphomas.
•The most common diseases resulting from deficiencies of the complement system
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C2 deficiency results in increased susceptibility to infections and SLE-like syndrome
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C1-inhibitor deficiency give rise to hereditary angioedema
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY,AND CLINICAL ASPECTS OF THE
IMMUNODEFICIENCY DISORDERS
AIDS- is and infectious disease caused by human immunodeficiency virus –HIV. It is characterized
by profound suppression the immune system and susceptibility to infection, neurological
disorders and malignancies.
HIV-1 and HIV-2 – two genetically different but closely related forms of human disease.
RNA viruses belonging to retrovirus family
HIV expresses cell surface protein gp 120 that binds to CD+ surface molecule of T-cells
proviral DNA synthesized by a reverse transcription in infected cells is integrated into the
host DNA
Mode of transmission
Sexual contact – homosexual, heterosexual
Potential inoculation – iv drug abuser, transfusion of blood and blood products
Passage from infected mother to child - transplacental spread, during delivery, during breast
feeding
The virus is carried by semen, contaminated blood or bodily secretions- any contact with them
carries a potential risk for transmission of the disease.
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY,AND CLINICAL ASPECTS OF THE
IMMUNODEFICIENCY DISORDERS
Pathogenesis of AIDS
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CD4+ T- cell, macrophages & dendritic
cells are primary targets for HIV
HIV binds to CD+ cells which acts as a
high-affinity receptor; infection requires
coreceptors CCR5 and CXCR4 - chemokine
receptors
Once internalized , viral genome undergo
reverse transcription leading to formation
of proviral DNA, - cDNA
cDNA in dividing cells intergrades in the
host genome
Proviral DNA is transcript and complete
virus particles are produce which may lead
to cell death
This results in reduction of CD+ T-cells,
persistent productive infection of
macrophages, monocytes and Langerhans
cells
Clinical phases of HIV infection
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Early, acute phase – self limited illness
3-6 weeks after infection. High level
of virus production and widespread
infection of lymphoid organs
Middle, chronic phase – no symptoms or
persistent lymphadenoptahy for
several years. Minor infection
Final, crisis – long lasting fever, severe
opportunistic infections, secondary
neoplasms, neurologic disease. It
usually develops after 7-10 years of
chronic phase.
Laboratory test to confirmed diagnosis of
AIDS
Seroconversion – presence of HIV
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antibodies in previously non-reactive
individuals – occurs within 6 mints of
exposure to HIV
Detection of infection during
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serological window before
seroconversion requires detection of
viral antigen or viral RNA
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY,AND CLINICAL ASPECTS OF THE
IMMUNODEFICIENCY DISORDERS
Opportunistic infection in AIDS
Opportunistic infections account for the
vast majority of deaths in patients
with HIV infection. These are:
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Pneumocytis carinii pneumonia
Candida albicans infection of mouth,
esophagus, vagina, lungs
Cytomegalovirus enteritis, pnuemonitis
Atypical mycobacterial infection (M.
avium intracellulare) of GI tract
Cryptococcus meningitis
Cryptosporidium enteritis
Neoplasms associated with HIV infection
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Kaposi sarcoma
Non Hodgkin lymphoma
Carcinoma of uterine cervix
Squamous carcinoma of the skin
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY,AND CLINICAL ASPECTS OF THE
IMMUNODEFICIENCY DISORDERS
Neurological consequences of HIV infection
Involvement of the CNS is common (4060%) and may present in several forms:
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Opportunistic infection
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Viral – CMV, Herpes simplex, fungal ,
protozoal
Aseptic meningitis
AIDS dementia complex
Neoplasms
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Lymphoma
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY AND CLINICAL
ASPECTS OF AMYLOIDOSIS
Amyloidosis
Amyloidosis is a group of diseases characterized by deposition of amyloid in
various organs
Amyloid is a proteinaceous substance deposited between cells in various organs
and tissue in a variety of clinical settings.
• The name derives from starch-like staining properties
• Amorphous, eosinophilic, hyline extracellular substance seen under microscope.
• Chemically diverse.
• Typical physical properties. All amyloidosis irrespective of their biochemical
composition form non-branching long fibrils (7.5-10mm) By electron diffraction
they are arranged in β-pleated sheaths.
• Congo-red staining is typical. Under polarized light, Congo-red stained amyloid
fibrils show an apple green birefringence.
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY AND
CLINICAL ASPECTS OF AMYLOIDOSIS
Biochemical forms of amyloid
• Al – amyloid formed by immunoglobulin light chains. This form of amyloid is found
in multiple myloma
• AA – amyloid associated protein synthesized by liver – SAA ( serum amyloid A).
This form of amyloid is seen in tissue of patients harboring chronic suppurative
infection
• Aβ - amyloid found in Alzheimer disease
The deposition of amyloid may occur as a primary disease – multiple myloma. Or as a
secondary form in the course of chronic inlammation or other disease.
The disease may be limited to a single organ, or systemic, and some forms may be
hereditary.
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY AND CLINICAL ASPECTS
OF AMYLOIDOSIS
Characteritics of primary amyloidosis
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Systemic deposits of AL type amyloid
Associated with plasma cell neoplasia
and B-cell lymphoma
Monoclonal gammapathy
Characteristics of secondary amyloidosis
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Underlying disease –e.g. Tuberculosis,
chronic ostemylitis, rheumatoid
arthritis, cancer, or condition- e.g.
heroin abuse
Widespread deposition of AA protein
in many organs
Amyloidosis of aging
• systemic deposition of amyloid in elderly patients
• frequent involvement of heart – cardiac amyloidosis
D 02-03/06
TO UNDERSTAND THE PATHOPHYSIOLOGY, LABORATORY AND CLINICAL
ASPECTS OF AMYLOIDOSIS
Morphological features in systemic amyloidosis
• kidney: enlarged. Pale, waxy. Glomerular mesengial, interstitial and vascular
deposition of amyloid
• spleen: enlarged with either nodular (follicular) depositions- sago spleen, or
map-like (red pulp) deposition – lardaceous spleen
• liver: hepatomegaly, extracellular amyloid with pressure atrophy of
hepatocytes
• small blood vessels in many organs contain deposits of amyloid. Amyloid
deposits in blood vessels can be observed in gingival or rectal biopsies –
commonly preformed to diagnosis of disease.
D 02-03/06