Transcript Immunodeficiency

IMMUNODEFICIENCIES
AIDS
Primary or
Congenital
Immunodeficiency
Secondary Immunodeficiency:
 Infection
 Renal failure, or protein losing
enteropathy
 Leukaemia or Lymphoma
Extremes of pediatric age:
premature, small for date
 Certain Drug Therapies
Secondary immunodeficiencies
(1) Iradiation-induced, drugs (steroids, other cytotoxic
drugs)
(2) AIDS (HIV target cells and immune dysfunction [see
Virology for other aspects of the viral infection])
(3)
Nutritional deficiency (reduced proteins, calories,
biotin, B12, Iron, Vit. A, Zinc; thymic atrophy
pathologic result)
(4) Autoimmune Disease ( frequent inflammatory
diseases are found in immunodeficient patients)
(5) Other (postviral, chronic infection, neoplastic
diseases)
Usually patients suffer from chronic
infections of opportunistic
pathogens
High incidence of cancer
Clinical features associated with
immunodeficiency
Feature frequency present and highly
suspicious:
 Chronic infection
 Recurrent infection (more than expected)
 Unusual microbial agents
 Incomplete clearing of infection
 Incomplete response to treatment
Clinical features associated with
immunodeficiency
Feature frequency present and highly
suspicious:
 Chronic infection
 Recurrent infection (more than expected)
 Unusual microbial agents
 Incomplete clearing of infection
 Incomplete response to treatment
Clinical features associated
with immunodeficiency
 Feature moderately suspicious
Diarrhea (chronic)
Growth failure
Recurrent abscesses
Recurrent osteomyelitis
 Feature associated with specific
immunodeficiency disorder
Telangiectasia
Partial albinism
Classification of
Immunodeficiencies:
 Antibody deficiencies
 Cellular deficiencies
 Phagocytic disorders
 Complement deficiencies
1. Signaling molecules in TCR ( T Cell Receptor)
activation
2. Key transcriptional factors of immune cells
3. Molecules and organs for lymphocyte
development
4. Antigen presentation
5. Phagocyte function
6. Cytokines and co-stimulation molecules
7. Immune cell migration and adhesion
8. Complement
9. DNA recombination and metabolism
Laboratory tests to assess
immune function
(1)
T cell: Enumeration (flow cytometry), functional
assays (mitogen response, MLR, DTH skin
tests)
(2) B cell: Enumeration, circulating antibody
levels
(3) Macrophage: Enumeration, functional
assays (nitroblue tetrazolium)
(4) Complement: Direct measurement of
complement components, complement
hemolysis assay
Primary B cell immunodeficiencies







(1) X-linked Agammaglobulinemia (Bruton's
syndrome); btk deficiency
(2) Common Variable Immunodeficiency (acquired
hypogammaglobulinemia)
(3) Selective IgA deficiency (most common
immunodeficiency disorder)
(4) Other (minor):
(a)
Transient hypogammaglobulinemia
of infancy
(b)
Selective deficiency of IgG
subclasses
(c)
Immunodeficiency with hyper IgM
Primary T cell
immunodeficiencies
Congenital thymic aplasia
(DiGeorge's Syndrome or Third and
Fourth Pharyngeal Arch Syndrome)
Combined B and T cell immunodeficiencies
(symptoms, description of defect, current
therapy)
(1) Severe Combined Immunodeficiency (SCID; a group of
genetically determined diseases)
(a) X-Linked combined immunodeficiency (accounts for 50-60%
of all SCID; defect in cytokine receptors)
(b) Adenosine deaminase deficiency (an autosomal recessive
SCID; accounts for ~20% of all SCID)

(c) Other mechanisms of SCIDs: Purine nucleoside
phosphorylase deficiency, TCR immunodeficiency, MHC
class I or II deficiency (Bare Lymphocyte Syndrome),
Defective IL-2 production
Primary phagocyte deficiencies


(1)
(2)
Neutropenia
Chronic Granulomatous
(3)
Leukocyte Adhesion Deficiency
Disease

Primary complement deficiencies
Deficiency of Complement Components
(a) Classic pathway: C1, C4, C2, C3
(b) Alternative pathway: Factor D,
Properdin
(c) MAC: C5, C6, C7, C8, C9
(d) Regulator proteins: Factors H, I, C1
inhibitor
(e) Hereditary Angioedema (C1INH
deficiency)
What is XLA?
 X linked agammaglobulinemia=‘prototypical
antibody deficiency’.
 First immunodeficiency described.
 Defect on the X chromosome
 affecting the Btk gene.
 Results in an absence or severe
 reduction in B lymphocytes and
 hence immunoglobulin of all types.
Clinical Findings
 Symptoms appear at 6-9 months of age (after loss
of maternal Ig) .
 Sites of infection: mucous membranes, ear (otitis
media), lungs (bronchitis/pneumonia), blood
(sepsis), gut (Giardia, or enterovirus), skin, eyes,
meningitis.
Also seen: joint problems, kidney
problems, neutropenia, malignancy
in older patients.
Patients with XLA repeatedly acquire infections with
extracellular pyogenic organisms such as:
Pneumococus
Hemophiluss
streptococus
Susceptibility to encapsulated
Bacteria
 H Influenzae
 S pneumoniae
Sinusitis
Pneumonia
Otitis Media
IgA Deficiency
 Clinical feature: Recurrent sinopulmounary
infection, Gastrointestinal disorders, Allergy,
Cancer and Autoimmune disease.
 IgA Deficiency and genetic factors: association
with HLA-A2, B8 and DW3 or A1 and B8.
 IgA Deficiency and drug.
 Serum IgA<5mg/dl but normal IgM and IgG
 Immunopathogenesis :arrest in the B cell
differentiation.
Selective IgG subclass
deficiency
 Total serum IgG levels are normal
 One or more subclasses are below normal.
 IgG3 deficiency is the most common subclass in
adults.
 IgG2 deficiency associated with IgA deficiency in
children.
 Pathogenesis: abnormal B cell differentiation.
 Some individual have recurrent bacterial infection.
CVID ( common variable
immunodeficiency) abnormalities
 CVID is a heterogenous group of disorders with
intrinsic B-cell defect or a B-cell dysfunction
related to abnormal T-cell B-cell interaction.
 Lack of inducible costimulator (ICOS) expression
by activated T cell which associated with lack of
T cell help for B cell differentiation, class
switching and memory B-cell generation.
 In 10-20% of families another member may have
selective IgA def.
DiGeorge Syndrome
 Defective development in thymus and
parathyroid that develop from third and
fourth Pharyngeal pouch
Thymic hypoplasia leading to variable
immunodeficiency. Other features:
Characteristic faces
Deletion in 22q11 in > 80%
Abnormal calcium homeostasis
Molecular mechanisms for constitutional
chromosomal rearrangements in humans
VCFS: CP, velopharyngeal insufficiency, small mouth, retrognathia, bulbous nasal tip,
microcephaly, concotruncal heart defects, MR, learning disabilities, short stature,
DGS: parathyroid hypoplasia, thymic hypoplasia and immune defect due to T cell deficit
DiGeorge Syndrome ( T deficiency)
Combined Immunodeficiencies:
 Combined immunodeficiency (CID)
 Severe combined immunodeficiency
(SCID)
 Omenn syndrome
 ADA (Adenosine Deaminase Deficiency)
 Ataxia-Telangiectasia syndrome (AT)
 Wiskott -Aldrich syndrome (WAS)
Common Features of Severe Combined
Immunodeficiency (SCID)
 Failure to thrive
 Onset of infections in the
neonatal period
 Opportunistic infections
 Chronic or recurrent thrush
 Chronic rashes
 Chronic or recurrent diarrhea
 Paucity of lymphoid tissue
WISKOTT-ALDRICH Syndrome
 X-linked
 Eczema ,thrombocytopenia ,bacterial infection
(polysaccharide antigen)
 Defective gene encode a cytoplasmic protein
expressed in BM derived cells interact with adaptor
molecule(Grb2)& G proteins regulate actin
cytoskeleton.
 Cell surface glycoproteins reduced ;CD43
 (or sialophorin) normally on Lymph .neut . Mac and
Platelet
 These alterations interfere with migration of Leuk. to
inflammation sites.
ATAXIA-TELANGIECTASIA
 Autosomal recessive
 Abnormal gait (ataxia)
 Vascular malformations (telangiectasia),
neurologic defects, tumors and ID
 ID may affect T&B cells
 IgA and IgG2 deficiency.
 T cell function is variably depressed.
 Gene responsible on chromosome 11
 Gene product may play a role in DNA repair
Phagocyte Deficiencies:
 Chronic granulomatous disease




(CGD)
Leukocyte adhesion deficiency
(LAD I)
Chediak- Higashi syndrome
IL-12 / IFN pathway deficiencies
Chronic or cyclic neutropenia
Acquired Immunodeficiency can be caused by :
HUMAN IMMUNODEFICIENCY
VIRUS (HIV)
Introduction
 Etiologic agent of Acquired
Immunodeficiency Syndrome (AIDS).
 Discovered independently by Luc Montagnier
of France and Robert Gallo of the US in 198384.
 Former names of the virus include:
 Human T cell lymphotrophic virus (HTLV-III)
 Lymphadenopathy associated virus (LAV)
 AIDS associated retrovirus (ARV)
Human Immunodeficiency Virus
Figure 9-13
Figure 9-14
Progression of AIDS
1. Infection
2. viremia (increase of the virus load in
blood)
3. immune response to HIV: generation of
Tc cells and antibody to HIV
(seroconversion)
4. temporary reduction of virus-infected
CD4 T cells (due to HIV-induced
apoptosis and T cell attack)
5. partial recovery of CD4 T cell number
6. gradual decrease of CD4 T cell number
over 2-15 years (clinical latency is a
period of active infection and CD4 T cell
renewal)
7. AIDS (CD4 T cell count < 200)
Acquired Immune deficiency syndrome
1. HIV infection through the host CD4 molecule and chemokine
receptors (CCR5 or CXCR4)
2. T cell activation is required for viral replication
3. Initial viremia and CD4 T cell number decrease (asymptomatic or
mild flu-like)
4. Anti-HIV response and CD4 T cell number recovery
5. Long clinical latency (2- 15 yrs): a period of active viral infection
and CD4 T cell renewal; gradual CD4 T cell number decrease
6. Immunodeficiency starts when the CD4 count is below 500 
Opportunistic infection
7. Death due to secondary infection
Gradual loss of CD4 T cells after infection
There are long-term non-progressors; some remain seronegative
Some people have mutant CCR5 thus can be resistant to HIV
Primary HIV Syndrome
 Mononucleosis-like, cold or flu-like symptoms
may occur 6 to 12 weeks after infection.









lymphadenopathy
fever
rash
headache
Fatigue
diarrhea
sore throat
neurologic manifestations.
no symptoms may be present
Primary HIV Syndrome
 Symptoms are relatively nonspecific.
 HIV antibody test often negative but becomes
positive within 3 to 6 months, this process is
known as seroconversion.
 Large amount of HIV in the peripheral blood.
 Primary HIV can be diagnosed using viral load
titer assay or other tests.
 Primary HIV syndrome resolves itself and HIV
infected person remains asymptomatic for a
prolonged period of time, often years.
Clinical Latency Period
 HIV continues to reproduce, CD4 count gradually
declines from its normal value of 500-1200.
 Once CD4 count drops below 500, HIV infected
person at risk for opportunistic infections.
 The following diseases are predictive of the
progression to AIDS:




persistent herpes-zoster infection (shingles)
oral candidiasis (thrush)
oral hairy leukoplakia
Kaposi’s sarcoma (KS)
AIDS
 CD4 count drops below 200 person is considered to have
advanced HIV disease
 If preventative medications not started the HIV infected
person is now at risk for:
 Pneumocystis carinii pneumonia (PCP)
 cryptococcal meningitis
 toxoplasmosis
 If CD4 count drops below 50:





Mycobacterium avium
Cytomegalovirus infections
lymphoma
dementia
Most deaths occur with CD4 counts below 50.
Opportunistic infections and malignancies kill HIV patients
Figure 9-22
Other Opportunistic
Infections

Respiratory system




Gastro-intestinal system






Cryptosporidiosis
Candida
Cytomegolavirus (CMV)
Isosporiasis
Kaposi's Sarcoma
Central/peripheral Nervous system







Pneumocystis Carinii Pneumonia (PCP)
Tuberculosis (TB)
Kaposi's Sarcoma (KS)
Cytomegolavirus
Toxoplasmosis
Cryptococcosis
Non Hodgkin's lymphoma
Varicella Zoster
Herpes simplex
Skin



Herpes simple
Kaposi's sarcoma
Varicella Zoster
Infants with HIV
 Failure to thrive
 Persistent oral candidiasis
 Hepatosplenomegaly
 Lymphadenopathy
 Recurrent diarrhea
 Recurrent bacterial infections
 Abnormal neurologic findings.
Laboratory Diagnosis of HIV
Infection
 Methods utilized to detect:
 Antibody
 Antigen
 Viral nucleic acid
 Virus in culture
ELISA Testing
 ELISA tests useful for:
 Screening blood products.
 Diagnosing and monitoring patients.
 Determining prevalence of infection.
 Research investigations.
Western Blot
 Antibodies to p24 and p55 appear earliest but
decrease or become undetectable.
 Antibodies to gp31, gp41, gp 120, and gp160
appear later but are present throughout all
stages of the disease.
 ‘Gold Standard’ for confirmation
Polymerase Chain Reaction
(PCR)
 Looks for HIV DNA in the WBCs of a person.
 PCR amplifies tiny quantities of the HIV DNA present,
each cycle of PCR results in doubling of the DNA
sequences present.
 The DNA is detected by using radioactive or biotinylated
probes.
 Once DNA is amplified it is placed on nitrocellulose paper
and allowed to react with a radiolabeled probe, a single
stranded DNA fragment unique to HIV, which will
hybridize with the patient’s HIV DNA if present.
 Radioactivity is determined.
Testing of Neonates
 Difficult due to presence of maternal IgG
antibodies.
 Use tests to detect IgM or IgA antibodies, IgM
lacks sensitivity, IgA more promising.
 Measurement of p24 antigen.
 PCR testing may be helpful but still not
detecting antigen soon enough: 38 days to 6
months to be positive.
Four FDA-approved Rapid HIV
Tests
Sensitivity
(95% C.I.)
Specificity
(95% C.I.)
OraQuick Advance
- whole blood
- oral fluid
- plasma
99.6 (98.5 - 99.9)
99.3 (98.4 - 99.7)
99.6 (98.5 - 99.9)
100 (99.7-100)
99.8 (99.6 – 99.9)
99.9 (99.6 – 99.9)
Uni-Gold Recombigen
- whole blood
- serum/plasma
100 (99.5 – 100)
100 (99.5 – 100)
99.7 (99.0 – 100)
99.8 (99.3 – 100)
Four FDA-approved Rapid HIV
Tests
Sensitivity
(95% C.I.)
Specificity
(95% C.I.)
99.8 (99.2 – 100)
99.8 (99.0 – 100)
99.1 (98.8 – 99.4)
98.6 (98.4 – 98.8)
100 (99.9 – 100)
99.9 (99.8 – 100)
Reveal G2
- serum
- plasma
Multispot
- serum/plasma
- HIV-2
100 (99.7 – 100)
The Move Toward Lower Pill Burdens
Regimen
Dosing
1996
Zerit/Epivir/Crixivan
10 pills, Q8H
1998
Retrovir/Epivir/Sustiva
5 pills, BID
2002
Combivir (AZT/3TC)/EFV
3 pills, BID
2003
Viread/ Emtriva/Sustiva
3 pills, QD
2004
Truvada/Sustiva
2 pills, QD
Daily pill burden
Combination drugs are effective in reducing HIV in patients
Figure 9-20
However this is not complete elimination