Immuno 3 - Secondary immune deficiencies and HIV 1 infection Flashcards
(45 cards)
o Commonest cause of secondary immune deficiency worldwide
• Malnutrition
B cell lymphoproliferative disorders associated with immune deficiency include
MM CML NHL MGUS - monoclonal gammopathy of uncertain significance
Clinical features of immune deficiences
- Infections – severe, persistent, recurrent, unusual
- Autoimmune conditions (immune cytopaenias)
- Allergic disease
- Persistent inflammation
- Cancer (particularly viral associated EBV, HHV-8)
First line ix if suspecting secondary immune deficiency/ immunodeficiency
FISH for an immunodeficiency
• FBC
o Hb
o Neutrophil/Lymphocyte/Platelet count
• Immunoglobulins o IgG, IgA, IgM, IgE o Low gG: Protein losing enteropathy Prednisolone >10mg/day o Low IgG + Low IgM: Monitor for B cell neoplasm Hx of exposure to rituximab o Low IgG + Low IgA Primary antibody deficiency
• Serum Complement
o C3, C4
o Screens for C1 inhibitory deficiency, Immune complex disease, Lupus
• HIV test
o 18-80 years
What is Goods’ syndrome?
Goods’ syndrome
- Thymoma and antibody deficiency
- Combined T and B cell (absent) defect
- CMV PJP and muco-cutaneous candida
- Autoimmune disease (Pure red cell aplasia, Myasthenia gravis, Lichen planus)
Other ix in secondary immunodeficiencies
U+Es
LFTs
Bone profile + Ca
Total protein + Albumin
Urine Protein: creatinine
Serum protein electrophoresis
o Separation of serum proteins by charge
o Detection of discrete bands
Monoclonal identified by immunofixation with labelled IgG, IgM, IgA anti-sera
Monoclonal protein associated with MM, WMG, NHL and MGUS
o SPE can miss free light chain disease
Serum free light chains
o Free light chain disease seen in 20% of MM cases
o Essential for work up of B cell lymphoproliferative disorders (SPE can miss free light chain disease)
WMG = Waldenstorm macroglobulinaemia
Secondary investigations for immune deficiencies
• Concentration of vaccine antibodies
o Tetanus toxin – protein antigen
o Pneumovax vaccine – carbohydrate antigen (all 23 serotypes or to individual pneumococcal serotypes)
o If reduced vaccine antibody levels:
Offer test immunisation with Pneumovax II + tetanus to investigate immune function
Looking at T cell independent activity
Failure to respond to vaccination:
• Part of dx criteria for a number of primary antibody deficiency syndromes
• Criteria for receipt of IgG replacement therapy for secondary antibody deficiency syndromes
• Analysis + quantification of lymphocyte subsets using flow cytometry o CD3+CD4+ T cells o CD3+CD8+ T cells o CD3-CD56+CD16+ NK cells o CD19+ B cells
Third line investigations for secondary immunodeficiencies
- Analysis of naïve + memory T and B cell subsets
- Assessment of IgG subclasses
- Determination of anti-cytokine and anti-complement antibodies
• Genetics
o Whole exome/Whole genome sequencing - ?primary or ?secondary immune defect
Which antibodies are responsible for the following conditions
SARS-CoV-2 infection
disseminated NTM (non-tuberculous mycobacteria) infection
cryptococcal infection
B cell lymphoproliferative disorders + SLE
o Anti-type 1 IFN antibodies (IFN-α and IFN-ω) SARS-CoV-2 infection
o Anti-type 2 IFN antibodies (IFN-γ) disseminated NTM (non-tuberculous mycobacteria) infection
o Anti-GM-CSF antibodies cryptococcal infection
o Anti-C1 inhibitor antibodies + acquired late onset angioedema B cell lymphoproliferative disorders + SLE
Management of secondary immune deficiency
- Treat underlying cause
- Advise on measures to reduce exposure to infection
• Immunisation
o Against respiratory viruses + bacteria
o Offer vaccines to household contacts
• Education to treat bacterial infections promptly
o May require higher + longer therapies courses
• Prophylactic antibiotics
o For confirmed recurrent bacterial infection
criteria for
IgG replacement therapy for secondary antibody deficiency syndromes
• Underlying cause of hypogammaglobinaemia cannot be reversed or reversal is contraindicated
OR
• Hypogammaglobulinemia associated with
o Drugs
o Therapeutic monoclonal antibodies targeted at B cells and plasma cells
o Post-HSCT
o NHL, CLL, MM or other relevant B-cell malignancy
AND
- Recurrent or severe bacterial infection despite continuous oral antibiotic therapy for 6 months
- IgG <4.0g/L (excluding paraprotein/monoclonal protein)
- Failure of vaccine response to unconjugated pneumococcal or other polysaccharide vaccine challenge
HIV
Time period between infection to symptomatic disease/AIDS
Highest risk of transmission
10 years
risk of transmission highest within the first 6 months
Mechanism of action of HIV
- Targets CD4+ cells
- Gp120 (initial binding) and gp41 (conformational change) binds to CD4+ T cells + HIV co-receptors
- Binds to CD4 + then chemokine co-receptor CCR5 or CXCR4
• Replicates via a DNA intermediate using reverse transcriptase – converts RNA into DNA which can be integrated into host cell’s genes
- Integrates into host genome
- HIV DNA transcribed into viral mRNA transcribed into viral proteins package + release of mature virus
• Gag protein – intrastructural support for HIV
HIV1 lineages
HIV-1 consists of 4 distinct lineages M, N, O, and P
Each lineage arose from independent transmission from chimpanzees (Group M,N,O) and gorillas (O,P)
Group M virus is pandemic, consists of 9 subtypes and 40 recombinant forms
What happens in HIV during acute phase chronic phase AIDS to
CD4 T cell counts in the blood
Mucosal CD4 t cells
Immune activation
CD4 T cell counts in the blood
acute phase - drop
chronic phase - small rise
AIDS - dramatic decline
Mucosal CD4 t cells
drop in acute phase, never recover
Immune activation
significant increase
What predicts disease progression in HIV
Degree of immune activation
o Degree of immune activation can predict progression of infection (independent of CD4+) + response to ART
Initial viral burden (viral load set point)
• 3-6 months after initial infection a steady state HIV-1 viral concentration is observed in blood viral load set point
• Progression to symptomatic HIV-1 infection stratified by VL set point
• Viral load set point correlated with long-term outcome
• Magnitude of VL set point influenced by
o Viral genotype
o CD8 T cell immune
o Host genetics (HLA, CCR5)
o Immune activation
Characteristic features of the immunology of HIV-1 infection
• CD4 T cell depletion
• Impairment of CD4 + CD8 T cell function – “exhaustion”
o Present but don’t work very well – don’t secrete antiviral inhibitory cytokines/chemokines, are not cytotoxic
• Disruption of lymph node architecture + impaired ability to generate protective T and B cell immune responses
• Loss of antigen-specific humoral immune responses
o Recurrent bacterial infections in sub-sacharan Africa are the main drivers of infection
• Chronic immune activation
How long does HIV need to integrate into T cells?
• Integration of HIV provirus in memory T cells within 72 hours of infection formation of long-lived reservoir of latent infection does not respond to current ART
How does HIV survive?
• Error prone nature of HIV RT short generation time of viral cycle + length of infection driving force for viral diversity
• Viral mutation
o Evasion of the CTL (cytotoxic T lymphocyte) immune responses
o Emergence of drug resistant virus in patients with inadequate drug treatment
What happens during the acute phase of HIV infection?
• Significant increase in HIV-1 viral load in blood
• Flu like symptoms in 70% of cases
o Infectious mononucleosis type picture
- Transient reduction in blood CD4+ T cells
- C8 T cell activation (CD38+ and HLA-DR+)
- Increase in CD8 T cell immune response coincides with drop in VL
- Induction of HIV-1 specific antibodies
How does HIV damage the immune system?
- HIV remains infectious even when Ab coated
- Activated infected CD4+ helper T cells –> killed by CD8+ T cells and are anergised (disabled)
- CD4 T-cell memory lost & failure to activate memory CTL
- Monocytes and dendritic cells –> not activated by the CD4+ T cells –> cannot prime naïve CD8+ CTL (due to impaired antigen presenting functions)
- Infected monocytes dendritic cells –> killed by virus or CTL
- Quasispecies are produced due to error-prone reverse transcriptase = these escape from immune response
- Effective immunity requires antibodies to prevent infection and neutralize virus, and sufficient CTL to eliminate latently infected cells
Diagnosis of HIV infection (7)
• 4th generation combined HIV-1 antigen/antibody tests
o Will detect infection 1 month post acquisition
• rapid point of care HIV-1 tests
o Results available within 20 mins
o Less sensitive than 4th generation test
• Assay detect o p24 antigen – part of nuclear capsid o gp41 – from HIV-1 Group O o gp160 – envelop protein on HIV-` o gp36 – HIV 2
• HIV-1 RNA tests
o In cases where HIV-1 serological tests are negative but there is high clinical suspicion of acute HIV-1 infection
• HIV-1 RNA and/or DNA tests
o Used to diagnose infection in children <18 months
• Screening test – detects anti-HIV ab via ELISA
• Confirmation test – detects ab via Western Blot
o A positive test requires the patient to have seroconverted (i.e. started to produce ab)
o This happens after around 10 weeks incubation
HIV specific tests
• HIV-1
o Viral load
o Genotype (for ART drug resistance)
o Tropism test to confirm co-receptor use in HIV-1 in patients who may be candidates for treatment with CCR5 antagonists
• HLA-B*5701 blood test
o To avoid prescribing Abacavir
o Risk of severe hypersensitivity in those with this allele (can die from it)
o to prevent hypersensitivity reaction with protease inhibitors
• Analysis of T cell counts
o CD4 T cell count + percentage – to stratify risk of infection
o CD4: CD8 t cell ratio
Infections + CD4 count
500 cells/mm3
400 cells/mm3
300 cells/mm3
200 cells/mm3
100 cells/mm3
50 cells/mm3
> 500
Community acquired organisms - HSV, zoster, pneumonia, bacterial skin infections, oral, skin fungal infections
400 cells/mm3
Kaposi’s sarcoma
Cutanous kaposis
300
Hairy leukoplakia
TB
<200 PCP Cryptosporidium Candida Fungal pneumonia
<100
Toxoplasmosis
Cryptococcus
Candida, HSV, CMV oesophagitis
<50 CMV Cryptococcus Lymphoma MAC (mycobacterium avium complex) Toxoplasmosis Visceral Kaposis
