Immunodeficiency Presentation PDF

Immunodeficiency Learning Objectives 1) In these videos I aim to cover: Examples of primary (inherited) immunodeficiency, their causes and manifestations. Examples of secondary (acquired) immunodeficiency, causes and symptoms. Basic detection, monitoring and treatment guidelines / pl...

Immunodeficiency Learning Objectives 1) In these videos I aim to cover: Examples of primary (inherited) immunodeficiency, their causes and manifestations. Examples of secondary (acquired) immunodeficiency, causes and symptoms. Basic detection, monitoring and treatment guidelines / plans for these conditions. 2) By the end of these videos you should be able to explain: The causes of both primary and secondary immunodeficiencies. How those causes manifest as symptoms and induce immune dysfunction in both primary and secondary immunodeficiencies. How basic laboratory investigations are used to diagnose and monitor the progress of patients before and after treatment for primary and secondary immunodeficiencies. Contents Primary immunodeficiency definitions and classifications and examples of these Secondary immunodeficiency and pathogenesis HAART and treatment of HIV and AIDS Primary immunodeficiency definitions and classifications Learning objectives What the WHO classifications of primary immunodeficiencies. How different immunodeficiencies present differently in the WHO classifications. The cause and detection of these diseases. Causes of Primary Immunodeficiency WHO classifications of immunodeficiencies 1. Phagocyte dysfunction 2. Complement abnormalities and deficiencies 3. B lymphocyte (humoral) defects and deficiencies 4. T lymphocyte Cell Mediated Immunity (CMI) defects and deficiencies 5. Combined B and T cell defects and deficiencies. Primary immunodeficiencies Hallmarks of Primary Immune Deficiencies Present from birth Symptoms can present from 1-2 months post partum Frequent and prolonged infection Rare infections Frequent medical intervention Usually symptoms start in childhood Developmental delay (DD) Failure to thrive (FTT) Treatments Risk : benefit ratio Risk of treatment Benefit of treatment Stem cell transplantation Replaces Aberrant cells Gene therapy does not work Clones outgrown by original cells 1. Phagocyte dysfunction Chronic Granulomatous Disease Patient presentation: Early onset symptoms show from 3 months+ Recurrent infection Failure to thrive Deep systemic infections Fungal infections (Aspergillosis, common) Inflammatory, Antibody and complement response normal. Dysfunction in phox genes (x-linked phox-91) 2. Complement abnormalities and deficiencies Patient presentation Symptoms start early recurrent infections Some developmental delay Severe bacterial infections X-linked and autosomal abnormalities Older presentation (generally) 2 years + Certain bacterial infections associated with different types N. meningitidis (Properdin deficiency) 2. Complement Deficiencies Treatments: Treat each infection as they occur ?Prophylactic antibiotic cover 3. Humoral deficiencies X-linked agammaglobulinaemia XLA (X-linked Agammaglobulinaemia) Formerly Bruton’s Agammglobulinaemia BTK deficiency (Bruton’s Tyrosine Kinase). Prevent’s B-cell development BTK required after pro-B cell for development. Also found in platelets, and monocytes X-linked diseases Patients Present with Recurrent Infection Failure to thrive Life threatening infection Developmental delay Pyogenic infection Low circulating numbers of T and B cells Taken from Immunology 6th edition, Roitt, Bro and Male, Mosby, London, 2001, page 304 4. T Lymphocyte CMI defects Di George Syndrome Presentation Recurrent serious infections 3 months plus Failure to thrive: despite feeding Facial abnormality Cardiac abnormality 4. T Lymphocyte CMI defects Di George Syndrome Diagnosis No thymus or minimal thymus present on ultrasound or MRI CD45+, CD3-, CD4-, CD8-, CD56+, CD19/20+ In Di George’s syndrome Cardiac Abnormality, facial dysmorphia, T cell deficit due to thymic hypoplasia, Cleft palate, Hypocalcaemia due to hypoparathyroidism resulting from 22q11 deletion Taken from Immunology, 6th edition, Roitt, Brostoff CATCH 22 and Male, Mosby, London, 2001, page 307 5. Severe combined Immunodeficiencies ADA SCID and X linked SCID Patients  Start to develop infection  Recurrent Life threatening Failure to thrive Opportunistic Unable to vaccinate Will usually result in death within 1st year of life Summary WHO categories of primary immunodeficiency and how they are classed The molecular and genetic causes of primary immunodeficiency The treatments of immunodeficiencies and how they are balanced against patient outcomes. Secondary immunodeficiency and pathogenesis Learning objectives. Understand the nature of the causes of secondary immunodeficiency Explore the timeline of HIV infection and how HIV progresses to AIDS Understand how the biology of HIV enables its hallmarks of infection and disease. Secondary immunodeficiency = Acquired Immunodeficiency 1. Immunomodulatory drugs 2. Diet 3. HIV Infection  HIV (Human immunodeficiency virus) First recognised in 1981. HIV virus isolated in 1983. First known human infection from 1959. Earliest AIDS cases 1960s and 1970s in Europe, USA and Haiti. Global infections 1980s and 1990s etc. Estimated that 39.9 (36.1 – 44.6) million people are infected with HIV worldwide (end 2023). 30.1 (23.8-39.7)million people were accessing antiretrovirals (end of 2023) Taken from: https://www.who.i nt/images/default- source/maps/hiv_a ll_2016.png?sfvrsn =792e6588_0 11/08/2024  HIV (Human Immunodeficiency Virus) 2 types of HIV – HIV-1 and HIV-2. HIV-1 is global common infection HIV-2 mainly restricted to W Africa. Zoonotic disease that arose in central and west Africa. HIV-1 from SIVcpz HIV-2 from SIVsm HIV is transmitted in cells (T cells, dendritic cells and macrophages) and body fluids (blood, semen, vaginal fluid, milk). 80% of infections are transmitted by sexual intercourse, other routes are contaminated needles and blood/blood products and perinatal transmission. HIV (Human Immunodeficiency Virus) HIV Virus: Enveloped retrovirus (100 – 200 nm dia) of lentivirus family. Comprises single stranded diploid RNA genome and proteins RT, integrase and proteases. HIV genes Link to paper explaining function genes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924471/  Virus Infection and Replication: Target cells that express CD4 (T cells, macrophages and dendritic cells) Gp120 binds to CD4 Conformation changes exposing chemokine receptor site in gp120. Binds co-receptor CCR5 or CXCR4. CCR5 on dendritic cells, macrophages and CD4+ T cells (R5 variants). CXCR4 on activated T cells (X4 variants). Gp41 fuses viral envelope with cell membrane and viral genome and associated proteins enter cell. Viral RT transcribes cDNA copy of viral genome -> integrated into host genome at LTR by viral integrase -> PROVIRUS.  Course of Infection: 1. Acute Phase – occurs 2 – 6 weeks after infection and results in seroconversion. 80% flu-like illness. 2. Asymptomatic phase – 2 – 20 years (mean 10 years). 3. Symptomatic phase – non-specific symptoms – fever, night sweats, diarrhoea, weight loss, skin infections. 4. AIDS – characterised by serious opportunistic infections and/or aggressive malignancy. Not untreated individuals progress to AIDS - some individuals live with chronic low level infection (asymptomatic)  HIV Pathogenesis: Understanding the factors that determine viral pathogenesis and disease progression is central to the treatment and prevention of HIV. Pathogenesis involves 2 phases – acute infection and chronic infection. During acute infection there is a large, rapid loss of memory CD4+ cells in MALT tissues mediated by HIV directly. This phase ends as immune responses (antibodies and CTL responses) control viral levels. During the chronic phase the immune system attempts to recover whilst still combating HIV. These phases are very different and thus may dictate different treatment/prevention approaches. HIV infection timeline  Initial Infection: HIV attaches to mucosa of genital tract / anus via one of 2 mechanisms: 1. Attachment to intraepithelial dendritic cells (DCs). 2. Attachment to epithelial cells expressing CCR5 -> infection of submucosal CD4+ T cells and DCs. DCs migrate to lymph nodes and transfer HIV to CD4+ T cells Thus, viral replication occurs initially in submucosal tissue and later in lymphoid tissues draining the mucosa.  In approximately 50% cases, late in infection the viral phenotype switches from R5 to X4 which is followed by a rapid decline in CD4+T cells and AIDS. Summary Know what cells are infected by HIV and what affect HIV has on them. Explain the immunological and physiological effects of HIV infection and its progression to AIDS Be able to explain the use and rationale of various tests at various stages of HIV infection HAART and treatment of HIV Learning objectives Understand the immune system’s response to HIV infection and the concentration of both viral particles and CD4+ cells in relation to each other. Understand how treatment of HIV can reduce the number of viral particles and why drug treatments need constant monitoring. Mechanism by which Virus evades Immune response 1. In accuracy of RT – every single possible point mutation in HIV genome arises on a daily basis. If mutations occur in key immunogenic epitopes, escape mutants arise which may have a growth advantage. Mutants may have compromised fitness. Mutations occurring in variable loops on gp120 generally avoid loss of fitness. 2. Obstruction of epitopes: Abs are directed against envelope glycoprotein gp120 and gp41. Epitopes are occluded by: a) glycosylation b) extension of variable loops from surface c) oligomerisation d) steric blocking 3. Downregulation of MHC class I by Nef. 4. Mutations in internal proteins to escape CTL response e.g Tat and protease. Mutations in viral protease and Tat can lead to loss of viral fitness. 5. Viral latency HIV does not replicate in resting T cells. Other factors: 1. HLA type: HLA-B alleles implicated in protection/susceptibility to AIDS. HLA-B*27, HLA-B*57 delayed progression to AIDS HLA-B*35 – accelerated progression to AIDS. HLA heterozygote advantage – maximum heterozygosity of class I loci associated with delayed onset of AIDS (homozygotes -> accelerated progression). Escape mutants avoid presentation – can induce loss of fitness. Revert to wild type when mutant transmitted to HLA discordant individual. 2. CCR5-Δ32 mutations: In Caucasians 1% population are homozygous and 20% heterozygous. Homozygotes are resistant to HIV infection and in heterozygotes onset of AIDS is delayed. Mutant allele of CCR5 receptor lacking 32 nucleotides forming a stop codon and premature translation and truncated receptor. Receptor does not migrate to cell surface. No other effects - ?cytokine redundancy. The strange case of Timothy Ray Brown The Berlin patient Diagnosed with HIV in 1995 Developed AML in 2007 Given allogeneic stem cell transplant Matched unrelated CCR5 mutated donor Donor cells cured patient of HIV Implications for treatment: 1. Infection – Chemokine analogues prevent binding to CCR5? In acute phase: 2. Vaccine – CTL and/or Abs may neutralise virus faster than natural response. In chronic phase: 3. Reconstitution of CD4+ T cell pool via cytokines (IL-2, IL-7). 3. Immune suppression. 4. Anti-viral targets – entry, replication and budding. These can be rationally designed. HAART already successful at controlling viral levels but very toxic and chance of drug resistant mutants. Summary The role of HAART in extending the life of HIV patients. How a patient’s genes can either exacerbate or slow-down or even cure HIV infection.