Bacterial Infections in Immunodeficiency Flashcards
We are constantly exposed to micro-organisms, yet disease due to micro-organisms (infection) is rare. Why?
We have evolved alongside many micro-organisms and for most bugs, the aim is to replicate, not to kill us! This has led to co-evolution of host immune system (recognition and response or tolerance) and organisms (immune evasion, virulence factors etc.).
When the balance between host immune system and micro-organisms is skewed, disease occurs. Give examples of how the balance can be skewed.
Reduced host immune system/immunocompromise
Increased organism virulence e.g. new strain
Why does a defect in one aspect of the immune system affect susceptibility to some, but not all micro-organisms?
Different aspects of the immune system act against different types of pathogen.
Give examples of physical barriers.
Skin, gut mucosa, respiratory tract, urinary tract, vagina
What cells and processes are involved in the innate immune system?
Phagocytes (neutrophils, macrophages, eosinophils etc)
Complement cascade
What cells are involved in humoral immunity?
B-cells, antibodies
What cells are involved in cell-mediated immunity?
T-cells, cytokines
Uses innate immune cells for effector function
How does the skin act as a physical barrier? (5)
Low pH, low free water, antimicrobial peptides, cell sloughing, resident commensals
How does the respiratory tract act as a physical barrier? (4)
Ciliated epithelium, antimicrobial peptides, cell sloughing, resident commensals
How does the gut mucosa as a physical barrier? (5)
Low pH, antimicrobial peptides, cell sloughing, commensal flora, tight junctions
How does the urinary tract as a physical barrier? (4)
Urethral sphincter, one way flow, antimicrobial peptides, cell sloughing
How does the vagina as a physical barrier? (2)
Commensal flora, pH
What is the main function of physical barriers?
Prevent invasion of micro-organisms – those that live in the environment and those that live in/on us. This includes bacteria, fungi, viruses and parasites.
How do phagocytes (innate immune system) recognise and respond to pathogens?
Phagocytes express pathogen recognition receptors (PRRs) e.g. TLRs, C-type lectins, dectin, and so recognise pathogen-associated molecular patterns (PAMPs) such as lipopolysachharide, peptidoglycan, beta-glucan. They also express receptors for complement & antibodies.
They respond with phagocytosis & intra-cellular killing, using Phago-lysosome fusion, ROS, bleach etc. They also release extracellular substances e.g. antimicrobial peptides, NETs etc.
In other words:
- Chemotaxis of phagocyte to microbes
- Adherence
- Ingestion of microbes by phagocytes
- Killing of microbes by enzymes and other chemicals, elimination
What type of organism(s) do phagocytes defend against?
Extracellular pathogens - bacteria, fungi, parasites
How does complement cascade (innate immune system) recognise and respond to pathogens?
Complement = series of plasma proteins
3 different recognition pathways:
- Classical pathway: C1q binds to antibody-antigen complex
- Mannose binding lectin pathway: binds to repeating sugars
- Alternative pathway: failure to inactivate intrinsic activation
Response:
- Opsonisation: phagocyte complement receptors (C3b)
- Chemotaxis: phagocyte complement receptors (C3a)
- Direct killing: C5-9 membrane attack complex
What type of organism(s) does complement system defend against?
Adjunct in the defence against extracellular pathogens - mainly bacteria.
NB – membrane attack complex (C5-9) is an essential component in the response to Neisseria species e.g. Neisseria meningitidis.
How does humoral immunity recognise and respond to pathogens?
Recognition is via B-cell receptors (antibody on surface of B-cell) – they recognise extracellular antigens (in the ‘humors’). This usually requires T-cell help, except polysaccharide antigens (marginal zone B-cells).
They respond by increasing production of antibodies (IgM, IgG, IgA, IgE). Then, neutralisation (bound Abs block binding of pathogens/toxins to cells), complement activation (C1q binds to Ag-Ab complexes), and antibody-dependent cytotoxicity (receptors on phagocytes for Fc portion of antibody).
What are the two main roles of humoral immunity?
Prevention of entry of intracellular pathogens (e.g. viruses, some bacteria) into cells Enhanced killing of extracellular pathogens (bacteria, fungi, and parasites esp. IgE vs. multicellular helminths).
How does cell-mediated immunity recognise pathogens?
T-cell receptor recognises intracellular antigens, presented on MHC molecules
What do CD4+ T helper cells recognise?
Antigens from within vesicles (e.g. phagocytosed bacteria) presented by antigen-presenting cells
MHC-II
What do CD8+ cytotoxic T cells recognise?
Antigens from within cell cytosol (e.g. viruses), presented by all nucleated cells
MHC-I
How do CD4+ T helper cells respond?
Th1: Stimulate antigen presenting cells to kill intracellular pathogens (e.g. phagolysosome fusion, production of ROS etc)
Th2: Stimulate B-cells to make antibodies
How do CD8+ cytotoxic T cells respond?
Kill cells expressing antigen, which are presumably infected by virus
Punch holes in the cell membrane (perforin)
Induce apoptosis (Fas ligand – Fas)
What is the main role of CD4+ T helper cells?
Th1: to help innate immune cells (esp. macrophages) kill or contain intracellular bacterial, fungal and protozoal pathogens. Esp. TB, Salmonella, Histoplasma, Leishmania, Toxoplasma
Th2: to help B-cells make antibodies to extracellular pathogens e.g. Bacteria, fungi, protozoa & helminths
What is the main role of CD8+ cytotoxic T cells?
To kill human cells infected with viruses
What is the exception to the rule regarding viruses and cytotoxic T cell response?
e.g. enterovirus & Hepatitis B –> humoral immune response is more important for their control than a cytotoxic T-cell response
Define a pathogen.
A micro-organism causing disease
Define a commensal organism.
A micro-organism that derives benefit from another
organism without causing damage
e.g. Staphylococcus epidermidis, Pneumocystis carinii
Define a primary pathogen and give some examples.
Common cause of disease in healthy hosts
e.g. S. aureus, S. pneumoniae
Define a opportunistic pathogen and give some examples.
Pathogen that is generally only able to cause disease in the setting of a weakened immune system
e.g. Staphylococcus epidermidis, Pneumocystis carinii
Define primary immunodeficiency.
Immune defect the patient is born with, often due to genetic mutation
Define secondary immunodeficiency.
Immune defect that is associated with / related to another condition
e. g. Iatrogenic – immune suppression due to treatment for another condition e.g. steroids, chemotherapy, ’ ‘biologics’
e. g. Non-iatrogenic – immune suppression related to a disease process - cancer, diabetes, malnutrition, infections e.g. HIV, HTLV, ‘sepsis’, post-measles
Multiple immune defects can (and often do) co-exist. Give an example.
Chemotherapy causes both mucositis (mechanical barrier issue) and neutropenia
How can the skin be damaged and what organisms can cause illness?
How: surgery, cannula, burns, trauma Organisms: - Skin flora (CoNS) - perineal flora - environmental, usually by inoculation (e.g. Bacillus, fungi)
How can the mucosa be damaged and what organisms can cause illness?
How: chemotherapy (mucositis), broad spectrum antibiotics (altered flora)
Which organisms:
- Translocation of normal, commensal flora (Gram-negative, Candida, anaerobes)
How can the resp tract be damaged and what organisms can cause illness?
How: intubation
Which organisms: from GI & upper resp tract
secretions e.g. Gram-negative, Candida
How can the urinary tract be damaged and what organisms can cause illness?
How: Urinary catheter
Which organisms: perineal flora (Gram-negative,
Candida)
How can the immunological function of the vagina be impaired and what organisms can cause illness?
How: broad spectrum antibiotics (altered commensals)
Which organisms: Candida
Innate immune defects with phagocytes - how?
Causes?
May be defects in number and / or function
Primary - Chronic granulomatous disease, Defects in neutrophil migration & granule release
Secondary:
Disease related e.g. AML, aplastic anaemia, diabetes
Chemotherapy-associated neutropenia
Impaired neutrophil function e.g. corticosteroids
What organisms are associated with impaired phagocytes?
Normal commensals in chemo-associated mucositis
Bacteria - S. aureus, Serratia, BCG-osis, Pseudomonas
Fungi - Aspergillus (esp. nidulans in CGD), Zygomycetes
Prophylaxis in impaired phagocytes?
Antibiotics e.g. quinolones Antifungals Interferon gamma (in CGD) Colony-stimulating factors Vaccination
Innate immune defects with complement - how?
Causes?
Primary - Defect in amount and / or function of complement components
Secondary - Eculizumab = monoclonal antibody vs. C5, used for PNH & acute rejection
Innate immune defects with complement - impact?
Meningococcal meningitis & meningococcal sepsis
Neisseria meningitidis infection
Innate immune defects with complement - prevention?
vaccination + prophylactic antibiotics
Humoral immunity defects - how?
Causes?
Primary - SCID, CVID, IgA deficiency, XLA, hyper IgM
Secondary - impaired B-cell number / function, e.g. CLL, splenectomy, corticosteroids, rituximab
Humoral immunity defects - impact/organisms?
Main risk = extracellular pathogens, usually bacteria
IgG deficiency –> ‘Encapsulated organisms’ - Strep pneumoniae, Haemophilus influenzae, Neisseria meningitis
IgA deficiency –> GI pathogens esp protozoa (giardia, cryptosporidium)
Humoral immunity defects - prevention?
Prophylactic antibiotics
Antibody replacement
Immunoglobulin derived from blood
Splenectomy - why at increased risk of encapsulated organisms?
There are a specific sub-set of B-cells that recognise
carbohydrate antigens - most of these reside in the marginal zone of the spleen.
Patients with no spleen are at significantly increased risk of infection due to encapsulated organisms (especially in the first couple of years post-splenectomy). B cells usually use T cell help, expect for with encapsulated organisms.
Splenectomy - prevention of infections?
Vaccination (preferably before splenectomy, with conjugate vaccines)
Prophylactic antibiotics e.g. PenV
Cell-mediated immune defects - how? Causes?
Primary - Most are combined, as T-cells important in for B-cell development e.g. SCID, Hyper IgM, Di-George
Secondary:
Disease related: infection (HIV), malignancy
Treatment related: anti-rejection medication, steroids, anti-TNF, stem-cell transplant, radiotherapy, ‘biologicals’
Malnutrition
Cell-mediated immune defects - impact?
Impaired response to intracellular infection
HIV and anti-TNF therapy as examples of a cell-mediated immune defects.
HIV targets CD4 cells, so biggest impact is on T-helper responses, but with knock-on effects to CD8+ and Th2 function.
Anti-TNF therapy targets one of the key effectors of Th1-mediated immune response, so biggest impact is on macrophage responses to intracellular pathogens.
Cell-mediated immune defects
Prevention?
Prophylactic anti-invectives e.g.
Bacterial: treatment of latent TB, cotrimoxazole (vs. listeria, nocardia)
Fungal: cotrimoxazole (vs. PCP)
Viral: aciclovir (vs. HSV & VZV)
Immunisations
Of patient – may have reduced efficacy
Of those around the patient – important
NB –know (and avoid) live vaccines
When to suspect a primary immunodeficiency?
Failure to thrive
Infections requiring iv antibiotics
Family history of PID
Four or more new ear infections within one year
Two or more new sinus infections within one year
Two or more months on at least two antibiotics
Two or more pneumonias within three years
Having frequent deep skin or organ abscesses
Thrush or cutaneous fungal infection for > six months
Two or more deep-seated infections, including septicaemia (blood poisioning), within three years.
