Immunopathology IV - Immunodeficiency Flashcards
(25 cards)
(OBJ) Define what is meant by “immunodeficiency” and name the two categories into which it is divided.
Immunodeficiency: a state in which the immune system’s ability to fight infectious disease is compromised or entirely absent
Two categories:
- Primary (congenital)
- Secondary (acquired)
(OBJ) List 4 X-linked and 2 (or 3) autosome-linked diseases that cause immunodeficiency.
X-linked:
- -XLA (Bruton’s)
- -Hyper-IgM syndrome
- -SCID
- -Wiskott-Aldrich Syndrome
Autosome-linked:
- -C1 inhibitor deficiency (hereditary angioedema): dominant
- -DiGeorge syndrome: recessive
- -SCID - ADA: recessive
(OBJ) List three causes of acquired immunodeficiencies.
Iatrogenic: chemotherapy, immunosuppressive therapy
Due to underlying medical condition: cancer, diabetes, renal disease, infection
HIV
(OBJ) Discuss the cause of Bruton’s X-linked agammaglobulinemia.
Humoral, X-linked
Failure of B cell precursors to develop into mature B cells
Cause: mutations in Bruton tyrosine kinase gene on X chromosome
–Btk required for signal transduction necessary for Ig light-chain rearrangement and B cell maturation
X-Linked Agammaglobulinemia (Bruton’s Agammaglobulinemia): signs and symptoms (7), prevalence in the population, vulnerable to what diseases (3)
Almost always in males
Decreased to absent B cells in circulation
Decreased serum Ig
Normal marrow B cell precursors
Normal T cell mediated reactions
Increased risk of autoimmune disease
Manifests around 6mo of age when maternal IgG is depleted
DISEASES:
- -Recurrent RT infections (pharyngitis, sinusitis, otitis, bronchitis, pneumonia) caused by bacteria normally opsonized by Abs (H. influenzae, S. pneumoniae, S. aureus)
- -Enteroviral encephalitis from enteroviruses typically neutralized by Abs (echo, polio, coxsackievirus)
- -Severe intestinal giardiasis caused by parasite normally resisted by secreted IgA (Giardia lamblia)
PREVALENCE: 1/100,000 male newborns
Common Variable Immunodeficiency: defect, signs and symptoms (3), prevalence in the population
Defect: normal B cells, but unable to differentiate into plasma cells
Signs/symptoms: hypogammaglobulinemia
- -Presentation resembles Bruton’s, but genders equally affected
- -Onset later in childhood or adolescence
PREVALENCE: 1/50,000
Isolated IgA Deficiency: defect, signs and symptoms (2), prevalence in the population
Defect: inability to class switch to IgA
Prevalence: 1/600 in European descent
S/S:
- -Everything intact except IgA
- -Increased risk of respiratory & GI infections
(OBJ) Name the life-threatening condition associated with IgA deficiency.
Severe anaphylactic reaction to IgA Abs during a transfusion (if a person is totally deficient)
Hyper-IgM Syndrome: defect, signs and symptoms (1), prevalence in population
Defect in ability of helper T cells to deliver activating signals to B cells --Mutation in CD40L - X-linked, required for class switching
S/S:
–Have IgM, but deficient in IgG, IgA, IgE
PREVALENCE: 1/1,000,000 (rare)
Briefly discuss treatment for humoral immunodeficiency syndromes.
IVIG - intravenous immunoglobulin replacement therapy
- -Given every 3-4 weeks based on body weight
- -Goal: prevent serious infection, achieve rate of infection comparable to general population
DiGeorge Syndrome (Thymic Hypoplasia): defect, signs and symptoms (4), prevalence in population
Defect: 22q11 deletion -> failure of development of 3rd and 4th pharyngeal pouches during embryogenesis -> no thymus -> loss of T cell-mediated immunity
S/S:
–Associated anatomical abnormalities
DISEASES:
–Bacterial sepsis (but generally not other bacterial infections)
–Viruses: CMV, EBV, severe varicella, chronic respiratory and intestinal infection
–Fungal and parasites: Candida, Pneumocystis jiroveci
PREVALENCE: 1/2,000-1/4,000
(OBJ) Identify the anatomic abnormalities associated with DiGeorge Syndrome. (3+10 others)
Tetany
Congenital heart defects
Lack of a thymus
Retrognathia or micrognathia Long face High and broad nasal bridge Narrow palpebral fissures Small teeth Asymmetrical crying face Downturned mouth Short philtrum Low-set, malformed ears Hypertelorism
(OBJ) Describe severe combined immunodeficiency syndrome (SCID) and name two molecular etiologies for it.
SCID: immunodeficiency takes out both T cells and B cells
- Cytokine receptor deficiency: involved in signal transduction for a variety of IL receptors, impacting T cell development
- -X-linked - ADA deficiency: accumulation of toxic derivatives impacting immature lymphocytes
- -Autosomal recessive
Severe Combined Immunodeficiency (SCID) – and subtypes: signs and symptoms (5), prevalence in population
Lymphopenia:
–Low/absent T cells
–Low/absent B cells
Hypogammaglobulinemia
High risk of viral, bacterial, AND fungal infections
Death in first year of life without bone marrow transplantation
PREVALENCE: 1/50,000 to 1/100,000
Wiskott-Aldrich Syndrome: defect, signs and symptoms (7), prevalence in population
Defect: X-linked recessive mutation in WAS protein (function unclear)
S/S: thrombocytopenia, eczema, immune deficiency
- -Low IgM, normal IgG, elevated IgA & IgE
- -No Abs to polysaccharide (blood type) Ags
- -Progressive T cell depletion
- -Bone marrow transplantation curative
PREVALENCE: 1/250,000
Genetic Deficiencies of the Complement System: defect, signs and symptoms, prevalence in population
- -C2 (1/10,000) = no increased risk of infection, but increased risk of SLE-like autoimmune disease
- -C3 (very very rare) = increased risk of bacterial infection
- -C5-9 (very very rare) = increased risk of Neisseria infection
(OBJ) Describe the disease hereditary angioneurotic edema and discuss its etiology.
Defect in C1 inhibitor -> unregulated C1, Hagemann factor, Kallikrein, and Plasmin -> mast cell degranulation, vasoactive peptide release
Disease: episodic edema of skin and mucosal surfaces (larynx, GI tract) due to stressors
PREVALENCE: 1/50,000 to 1/150,000
(OBJ) Diagram the HIV genome and name the functions of the genes encoded therein. [MEMORIZE the HIV genome and the role each component of the genome plays in infection and
disease – it will be on the next quiz and the final exam! (especially LTR)] (1 LTR, 4 gag, 3 pol, 2 env, 2 regulatory genes, 4 accessory genes)
HIV: retrovirus
–Immunosuppression -> opportunistic infection, secondary neoplasm, neurologic manifestations
LTR = transcription initiation sites, binding for TAT
gag
- -matrix (p17)
- -capsid (p24) (important seroprotein)
- -nucleocapsid (p7)
- -p6
pol
- -Reverse transcriptase: RNA -> DNA
- -Protease: cleaves precursor polypeptides
- -Integrase: integrates viral DNA -> host cell DNA
env
- -Gp120: attachment to CD4 receptor and chemokine co-receptors (CCR5 or CXCR4)
- -Gp41: Fusion with host cell
Regulatory replication genes
- -tat: activation of transcription of viral genes
- -rev: transport of late mRNAs from nucleus to cytoplasm
Regulatory accessory genes:
- -nef: decreases CD4 proteins and MHC I proteins on surface of infected cells; induces death of uninfected cytotoxic T cells
- -vif: enhances infectivity by inhibiting the action of APOBEC3G (enzyme that causes hypermutation in retroviral DNA)
- -vpr: transports viral core from cytoplasm into nucleus in nondividing cell
- -Vpu: enhances virion release from cell
What happens in primary infection with HIV?
Virus enters blood through mucosal tears
Infects T cells, DCs, and MOs
Infection becomes established in lymphoid tissues
List four mechanisms of immunodeficiency in HIV.
- Direct cytopathic effect of replicating virus
- Colonization of lymphoid tissue -> progressive destruction
- Chronic activation of uninfected cells -> activation-induced cell death
- Killing of infected cells by CTLs
(OBJ) Discuss the natural evolution of HIV-1 infection in an untreated host. (6 stages)
- Viral dissemination -> host immune response
- –This is the immediate viremic period, possible flu-like symptoms - Seroconversion detectable 3-7 weeks post-exposure
- CTLs contain initial infection, viremia decreases
- –Become asymptomatic, low viral load - Virus evades immune system, CD4 T cell count decreases
- CD4 count hits a critical low point -> exponential increase in viral load
- AIDS
How does HIV evade the host immune system? (3)
Frequent mutations because of error-prone replication
Glycan shield - prevents Ab binding
Point mutations, insertions, deletions alter positioning of sugars -> ever-changing disguise
Identify the clinical features of AIDS, i.e. HIV infection that has become immunosuppressive. (5 category B, 5 category C)
AIDS-indicator conditions: conditions that are associated with AIDS/HIV, assigned to categories A, B, or C
Category B: indicative of AIDS, but also occur in others
- -Thrush (Candida)
- -PID
- -Hairy leukoplakia
- -Idiopathic thrombocytopenia
- -Shingles
Category C: very specific to AIDS
- -CMV pneumonia
- -Mycobacterium avium-intracellulare infection of lymph nodes
- -Toxoplasmosis in brain
- -Pneumocystis jiroveci in lung
- -Kaposi’s sarcoma: skin (or mouth) malignancy
Recognize populations at risk for HIV infection.
Men who have sex with men
People who engage in IV drug use
Sex workers
Heterosexual contact
