Immunodeficiency

What is immunodeficiency?

Absence of a sufficient immune response, either primary (congenital) or secondary (acquired)

What are the 5 classifications of immunodeficiency?

Humoral, cellular, combined, phagocytic dysfunction, and complement deficiencies

At what age do most primary immunodeficiencies become apparent, and why?

Around 6 months, because maternally-transferred IgG has been cleared by then

Name 4 causes of secondary (acquired) immunodeficiency

Infection, therapeutic treatments (e.g. chemo), cancer, and malnutrition

Why do humoral immunodeficiencies cause infections with encapsulated bacteria specifically?

Encapsulated bacteria resist phagocytosis unless coated (opsonized) by antibody first; without antibodies they evade clearance

Name the 3 classic encapsulated bacteria causing infection in humoral immunodeficiency

Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus

What lung complication develops from untreated recurrent pneumonia in humoral immunodeficiency?

Bronchiectasis (obstructive lung disease from destroyed airway elasticity)

Who first described immunodeficiency, and when?

Colonel Ogden Bruton, 1952, in a 9-year-old boy with no measurable antibodies

What is the modern name for Bruton agammaglobulinemia?

X-linked agammaglobulinemia (XLA)

What is the genetic pattern of XLA?

X-linked recessive

What is the underlying defect in XLA?

Pre-B lymphocytes fail to differentiate into mature B-lymphocytes or plasma cells, due to defective lymphopoiesis

What immunoglobulin class is characteristically low in XLA?

IgG

At what age is XLA usually diagnosed?

Between 5 and 36 months

Besides bacteria, what other pathogens cause diarrhea in XLA patients?

Giardia and Campylobacter

What is the mainstay treatment for XLA?

Pooled immunoglobulin (IV or subcutaneous)

Why is palivizumab given to some XLA patients?

It's a monoclonal anti-RSV antibody used because RSV can cause fatal pneumonia in XLA patients

What is Common Variable Immunodeficiency (CVID)?

A primary B-lymphocyte deficiency with low serum immunoglobulin, due to defective antibody synthesis or secretion

How does CVID differ from XLA in terms of B-cell numbers?

CVID patients can have low, normal, or above-normal circulating B-cell counts, unlike the absent B-cells in XLA

What drug is used in CVID to reduce Giardia-associated diarrhea?

Metronidazole

Why do T-cell (cellular) immunodeficiencies increase risk from live attenuated vaccines?

Without T-cell control, the weakened vaccine organism can regain virulence and cause active infection

What is the underlying defect in DiGeorge syndrome?

Complete or partial absence of the thymus, leading to defective T-lymphocytes

Are antibody levels normal in DiGeorge syndrome?

Often yes, but patients fail to mount responses to T-dependent antigens

What treatment restores immune function in DiGeorge syndrome?

IL-2, which mimics the thymic environment for T-cell maturation

What is the hallmark lab finding in SCID?

Severe lymphopenia with diminished/absent CD3, CD4, and CD8 lymphocytes

Which cell lineages are affected in SCID?

Both T-cells and B-cells

What opportunistic infections are common in SCID?

Pneumocystis carinii pneumonia and Candida albicans

What gene defect causes the common X-linked form of SCID?

Defective gamma chain of the IL-2 receptor, shared with IL-4, IL-7, IL-11, and IL-15 receptors

Which cytokine using the common gamma chain is most critical for early T-cell development?

IL-7

What is the sex ratio of SCID incidence and why?

3:1 male to female, because it is X-chromosome linked

What is the only curative treatment for SCID?

Bone marrow transplantation or gene therapy

What is the defect in Chronic Granulomatous Disease (CGD)?

Defective enzymes (NADPH oxidase) needed to generate toxic oxygen metabolites that kill ingested microbes

Why do phagocytes fail to kill microbes in CGD despite normal phagocytosis?

They can engulf microbes but lack the oxidative killing mechanism to destroy them intracellularly

When is interferon-gamma treatment recommended in CGD?

In patients who retain some residual superoxide (O2-) production

What is the only curative therapy for CGD?

Human stem cell transplantation

Which complement deficiencies are associated with systemic lupus erythematosus (SLE)?

C1, C4, and C2

What is the role of C3 and C5 in the complement system?

Immune adherence, opsonization, chemotaxis, and activation of the inflammatory response

What is the consequence of C3 deficiency?

Increased risk of bacterial infections

What is the consequence of C5 deficiency?

Intractable diarrhea and recurrent fungal and gram-negative bacterial infections

Which complement deficiencies specifically increase risk of disseminated Neisseria infections?

C5, C6, and C7 deficiencies

In what year and where were the first AIDS cases identified?

1981, Los Angeles

What two conditions were the first AIDS cases characterized by?

Pneumocystis pneumonia and Kaposi's sarcoma

In what year was HIV identified as the cause of AIDS?

1983

What type of virus is HIV?

An enveloped human retrovirus of the lentivirus family

Which HIV strain causes over 90% of infections worldwide?

HIV-1

Where is HIV-2 mostly found and how does its virulence compare to HIV-1?

Western Africa; it is less virulent than HIV-1

Name the three key enzymes carried by HIV

Integrase, protease, and reverse transcriptase

What are the two key HIV envelope glycoproteins and their functions?

gp120 (binds CD4 receptor) and gp41 (transmembrane protein enabling fusion)

Which cells are potential targets for HIV infection?

Any CD4-expressing cell: macrophages/monocytes, dendritic cells, and CD4+ T cells

Which coreceptor does macrophage-tropic HIV use?

CCR5

Which coreceptor does lymphotropic HIV use, and what CD4 density does it require?

CXCR4; requires high CD4 density

What happens to viral RNA once HIV enters a host cell?

It is reverse transcribed into DNA by reverse transcriptase, which then integrates into host chromosomal DNA

What is a provirus?

Viral DNA integrated into the host cell's chromosome, which may remain latent or become active

Why can macrophages and dendritic cells act as HIV reservoirs?

They are not usually killed by HIV, so they survive and transport virus to other tissues like lymphoid tissue and the CNS

Why does HIV have such a high mutation rate?

Reverse transcriptase lacks proofreading ability, and retroviruses have a high mutation rate compared to DNA viruses

How many HIV particles are generated per day, and what is their half-life?

About 100 billion per day, with a half-life of about 6 hours

What is the daily net loss of CD4+ T cells despite compensatory production?

At least 20 million CD4+ T cells per day

What is the approximate peak viral load in blood plasma during Phase 1 of HIV infection?

More than 10 million viral RNA copies per ml

What is viremia?

The presence of virus in peripheral blood

What is seroconversion?

The appearance of detectable antibodies specific to HIV proteins

What is the window period in HIV infection?

The period (about 5-10 weeks after infection) during which no antibody is yet detectable despite infection

What characterizes Phase 2 (chronic latent phase) of HIV infection?

Continued low-level viral replication mainly in lymph nodes, controlled partly by CD8+ T cells, with few symptoms

What happens to the CD4:CD8 T-cell ratio as HIV disease progresses?

It reverses from the normal ratio of approximately 2 to an inverted ratio

Name early signs of declining immunity seen in Phase 2 of HIV infection

Persistent Candida albicans infections, fever, persistent diarrhea, oral leukoplakia, shingles

What CD4+ T cell count defines clinical AIDS in the US?

Below 200 cells/µl

What are the three categories of AIDS-defining conditions?

Opportunistic infections, unusual malignancies, and general debilitating syndromes

What virus is associated with Kaposi's sarcoma in AIDS patients?

Human herpesvirus 8 (HHV-8)

What genetic factor gives about 1% of the population resistance to HIV infection?

A major deletion in CCR5, preventing the coreceptor from appearing on the cell surface

What are long-term nonprogressors?

HIV-infected individuals who remain symptom-free with stable CD4+ counts, sometimes surviving over 25 years

What body fluids carry the highest concentration of infective HIV?

Blood (1,000-100,000 virions/ml) and semen (10-50 virions/ml)

What percentage of pediatric AIDS cases result from mother-to-infant transmission?

More than 80%

What is the riskiest sexual route of HIV transmission?

Anal-receptive intercourse

Is HIV transmitted through casual contact, insects, or saliva?

No

What test is used to screen for HIV antibodies, and what confirms a positive result?

ELISA screens; Western blot confirms by detecting antibodies to individual viral proteins

Why are antibody tests unreliable in early infection and in infants of HIV-positive mothers?

Early infection: antibodies haven't formed yet (window period); infants: maternal antibodies cross the placenta causing false positives

What test detects viral RNA or proviral DNA directly, bypassing the antibody window period?

Nucleic acid testing (NAT), using methods such as PCR

What CD4 count range is not associated with opportunistic infections?

Above 500 cells/µL