Ch 6: Immunopathies (Part 5 - Immunodeficiency syndromes) Flashcards
Name the 2 types of immunodeficiency syndrome you can have.
Primary = genetic
Secondary = acquired (ex: HIV)
In general, what infectious diseases can you get with B-cell deficiencies?
Pyogenic bacterial infections
Enteric bacterial and viral infections
In general, what infectious diseases can you get with T-cell deficiencies?
Viral and other intracellular microbial infections (eg. pneumocystis jiroveci, other fungi, nontuberculous mycobacteria)
Some cancers (eg. EBV associated lymphomas, skin CA)
In general, what infectious diseases can you get with Innate immune deficiencies?
Variable - pyogenic, bacterial, anf viral infections
Name some innate immunodeficiencies affecting leukocytes.
Chediak Higashi syndrome
Chronic Granulomatous disease
What is Chediak Higashi syndrome?
Autosomal recessive
Failure of phagolysosomal fusion
Increased bacterial infection
Fatal w/o stem cell transplant
How can you detect Chediak Higashi histologically?
You can observe the failure of fusion on peripheral smear
Giant granules seen
Defects in melanocytes or grey hair streaks
What is chronic granulomatous disease?
Common mechanism = failure of superoxide production within phagocytes
Accumulation of macrophages “walls off” infection
Name some innate immunodeficiencies affecting complement.
Membrane attach complex deficiency
Hereditary angioedema? (not really, but…)
What is membrane attack complex deficiency?
Without final MAC, lysis of microbial membrane can’t occur
Happens when any of C5, 6, 7, 8, 9 are affected
Nisseria infections are common
Results in meningitis
What is hereditary angioedema?
Autosomal dominant
Deficiency of C1 inhibitor
Complement system goes nuts and you see increased in complement
Episodes of angioedema
What are some symptoms of hereditary angioedema?
Swelling of lips Swelling of airway Huge mucosal folds - intestine Swelling of genitals Dysuria Cutaneous edema
Name some adaptive immunodeficiencies affecting lymphocyte maturation.
Severe Combines Immunodeficiency (SCID)
Digeorge syndrome
X-linked Agammaglobulinemia
What is SCID? What are the 2 forms of inheritance?
Deficiency in both B cell and T cell lineages due to defect in T-cell function
2 forms = X-linked and Autosomal recessive
Describe the X-linked version of SCID.
Affects MALES
Mutations in IL receptors
T-cell reduced in number
B-cells present but unable to make Ab without T-cell help
Describe the autosomal recessive version of SCID.
Adenosine deaminase deficiency = MOST COMMON
Accumulation of toxic purine metabolites
Blocks T-cell formation
Some B-cell influence, but lacks helper T-cells to activate humoral response
How can you treat SCID?
Stem cell transplantation
Gene therapy
What is DiGeorge syndrome?
Primary deficiency of T-cell due to failure of dev of pharyngeal pouches 3 and 4:
Affects thymus, parathyroid, heart, and great vessels
How is DiGeorge inherited? What chromosome is associated with the disease?
May be inherited in sporadic and familial pattern
Many cases are 22q11 deletions
What are some physical manifestations of DiGeorge syndrome?
Facial and palatal abnormalities (micrognatia)
Cardiac abnormalities (tetralogy of fallout, trunks arteriosus)
Tetany - (not having enough calcium b/c parathyroid affected)
Immune deficiency
T cell def.
Humoral def if T-cell function if poor enough
What is X-link agammaglobulinemia?
Defect in Bruton tyrosine kinase (BTK) gene on X-chromosome - inability of pre-B cells to mature
Risk for infection increases after maternal abs wane, may even present in late childhood
What diseases can you get with agammaglobulinemia?
Encapsulated bacteria (streptococcus, pseudomonas, homophilus influenza type B)
Viruses
Protozoa (Giardia lamblia)
Name some adaptive immunodeficiencies affecting lymphocyte activation/function.
Hyper IgM syndrome
Common Variable Immunodeficiency (CVID)
IgA deficiency
What is Hyper IgM syndrome?
Encapsulated bacterial infections predominate due to lack of opsonizing antibodies
CD40/40L mutations Interferes with T-cell helping B-cells to class switch
Increase IgM levels, but lower levels of other classes
How do you treat Hyper IgM syndrome?
IVIG
Stem cell transplantation
What is CVID?
Multiple disorders resulting in hypogammaglobulinemia
Most common primary immunodeficiency
Encapsulated bacterial infections like X-linked agammaglobulinemia
Disease of exclusion
Later presentation
What diseases can you get with CVID?
Recurrent sinus and pulmonary infection (pyogenic bacteria)
Granulomas
Chronic diarrhea (Giardia lamblia)
Autoimmune disease (Anemia, thrombocytopenia)
What is IgA deficiency?
Can occur in familial and acquired forms
Loss of IgA means less defense against inhaled and ingested pathogens
What diseases can you get with IgA deficiency?
Sinus and respiratory infections Urinary bladder infections Gastrointestinal infections Autoimmune disease and allergies Anaphylactic reaction against red cell transfusion
How can you determine if someone have IgA deficiency with blood transfusion?
Transfusion-related anaphylaxis
Red cell washing can prevent reactions
Name some immunodeficiencies associated with systemic disease.
Wiskott Aldrich Syndrome
Ataxia telangiectasia
What is Wiskott Aldrich syndrome? What gene is involved? What is the treatment?
Triad of:
Thrombocytopenia
Eczema
Recurrent infections
WASP gene mutation
Tx = Stem cell transplant
What is ataxia telangiectasia?
Neurodegenerative disease = ataxia
Vascular malformation = telangiectasia
Immune deficiency - IgA and IgG
Autosomal recessive inheritance
What diseases can you get with ataxia telangiectasia? What gene is involved?
Respiratory infections
Autoimmune disease
Cancer (lymphoma)
ATM gene mutation = defective DNA repair
Under what clinical conditions can you see secondary immunodeficiency?
Cancer Malnutrition = DM Metabolic disease Chronic illness Treatment-related = Chemotherapy, radiation, immunosuppression
AIDS!
What is AIDS?
Aquired immunodeficiency syndrome
Manifestation of what occurs when HIV affects body to degree where immune dysfunction results in:
Opportunistic infection
Secondary neoplasms
Neurologic manifestations
Who can get AIDS?
Homosexual men
Blood transfusion recipients
Infants/female
Where is AIDS coming from?
Retrovirus
Lentivirus family
How can sexual transmission spread HIV?
Male to Male or Male to Female
Female to male less so
Breaching mucosal barrier (anal or vaginal) introduces virus to bloodstream or infects mucosal dendritic cells
What is the synergistic effect of HIV and non-HIV STDs?
Inflammation
Ulceration
How does HIV spread through the parenteral route?
Intravenous drugs (most common form) Transfusions
How can HIV spread from mother to child?
In utero through placenta to fetus
During delivery with contact of secretions in birth canal
After birth with ingestion of breast milk
What is the risk of “seroconversion” (contracting a disease from pt) after needle stick accident in regards to HIV and Hepatitis B?
HIV = 0.3%
Hep B = 30%
Describe the structure and content of HIV and how we can use these to test fro HIV.
Capsid proteins (p24) - test for p24 Ag
Glycoproteins (gp120, gp41) - important for attachment= good drug and vaccine targets
Viral enzymes (protease, reverse transcriptase, integrase)
HIV-1 RNA genome (gag, pol, env retroviral genes)
What is the LTR gene of HIV responsible for?
Initiates transcription, binds transcription factors
What is the gag gene of HIV responsible for?
Encodes for proteins inside the virus
What is the env gene of HIV responsible for?
Encodes for surface glycoproteins
What is the pol gene of HIV responsible for?
Encodes for viral enzymes
Describe how HIV enter a cell.
HIV uses a CD4 molecule for a receptor
Coreceptors = CCR5, CXCR4
gp120 binding to CD4 allows secondary binding to co-receptor
After binding occurs, gp41 can use fusion peptide to drill into host cell membrane, inserting the viral genome
Describe what happens after HIV enter a cell.
Reverse transcriptase synthesizes proviral DS DNA from original RNA genome
Integrase inserts the proviral DNA sequence into host genome
Host cell activation occurs, triggering LTR to initiate transcription of HIV viral RNA
