Primary orCongenital

Immunodeficiency

Secondary Immunodeficiency:

Infection Renal failure, or protein losing enteropathy

Leukaemia or LymphomaExtremes 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 cells3. Molecules and organs for lymphocyte

development4. Antigen presentation5. Phagocyte function6. Cytokines and co-stimulation molecules7. Immune cell migration and adhesion8. Complement9. 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) Neutropenia (2) Chronic Granulomatous

Disease (3) Leukocyte Adhesion

Deficiency

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 chromosomeaffecting the Btk gene.Results in an absence or severereduction 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.

Pneumococus

streptococus

Hemophiluss

Patients with XLA repeatedly acquire infections with extracellular pyogenic organisms such as:

Susceptibility to encapsulated Bacteria

H Influenzae

S pneumoniae

Otitis Media

Pneumonia

Sinusitis

IgA DeficiencyClinical 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 Defective development in thymus and parathyroid that develop from and parathyroid that develop from third and fourth Pharyngeal pouchthird 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 constitutionalchromosomal 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)

Failure to thriveFailure to thrive Onset of infections in the Onset of infections in the neonatal periodneonatal period Opportunistic infectionsOpportunistic infections Chronic or recurrent thrushChronic or recurrent thrush Chronic rashesChronic rashes Chronic or recurrent Chronic or recurrent diarrheadiarrhea Paucity of lymphoid tissuePaucity of lymphoid tissue

Common Features of Severe Common Features of Severe Combined Immunodeficiency (SCID)Combined Immunodeficiency (SCID)

WISKOTT-ALDRICH SyndromeX-linkedEczema ,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 PlateletThese 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 :

Introduction

Etiologic agent of Acquired Immunodeficiency Syndrome (AIDS).

Discovered independently by Luc Montagnier of France and Robert Gallo of the US in 1983-84.

Former names of the virus include: Human T cell lymphotrophic virus (HTLV-

III) Lymphadenopathy associated virus (LAV) AIDS associated retrovirus (ARV)

Figure 9-13Human Immunodeficiency Virus

Figure 9-14

Progression of AIDS1. 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.

Figure 9-22

Opportunistic infections and malignancies kill HIV patients

Other Opportunistic Infections Respiratory system

Pneumocystis Carinii Pneumonia (PCP) Tuberculosis (TB) Kaposi's Sarcoma (KS)

Gastro-intestinal system Cryptosporidiosis Candida Cytomegolavirus (CMV) Isosporiasis Kaposi's Sarcoma

Central/peripheral Nervous system 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.)

Reveal G2 - serum - plasma

99.8 (99.2 – 100)

99.8 (99.0 – 100)

99.1 (98.8 – 99.4)

98.6 (98.4 – 98.8)

Multispot - serum/plasma - HIV-2

100 (99.9 – 100)

100 (99.7 – 100)

99.9 (99.8 – 100)

The Move Toward Lower Pill BurdensDosing Daily pill

burdenRegimen

1996

Zerit/Epivir/Crixivan

10 pills, Q8H

20023 pills, BIDCombivir (AZT/3TC)/EFV

1998Retrovir/Epivir/Sustiva

5 pills, BID

2003 3 pills, QDViread/ Emtriva/Sustiva2004 2 pills, QDTruvada/Sustiva

Figure 9-20Combination drugs are effective in reducing HIV in patients

However this is not complete elimination