Lecture 26: Infection and Immunity Flashcards
A 10 month old NZ European infant girl attends the paediatric outpatient department because the Plunket nurse and her mother are concerned that she is not gaining enough weight. Her weight at the age of 6 months was on the 25th percentile and now is on the 2nd percentile.
Subsequently:
- Recurrent infections since 1 year old
- Pneumocystis carinii pneumonia when 3 years old
- Severe sinus infection with β-haemolytic streptococci (expect granulocytosis) when 5 years old
Blood shows:
- White Blood Cells: 4.2x109/l (5-11)
- Neutrophils: 1 x 109/l (1.8-7)
- Lymphocytes: 2.3 x 109/l (1.5-3.5)
- Monocytes: 1.2 x 109/l (0-1)
Serum immunoglobulin tests shows:
- IgM: 21g/l (normal 7.5-15)
- IgG: 2.5g/l (normal 60-150) *
- IgA: 0 g/l (normal 5-12.5) *
Peripheral blood lymphocytes shows:
- CD19: 11% (sIgM and sIgD only)
- CD3: 87%
- CD56: 2%
- Activated T cells didn’t bind soluble CD40
Why high IgM but no antigen-specific IgG? Why no sIgG on B cells? Why elevated anti-A and anti-B Abs?
What is her diagnosis?
Diagnosis is hyper IgM syndrome (CD40Ligand mutation)
So B cell development is fine
T cell development is fine up until a point but they can’t communicate with one another. Rather than being able to produce IgM, G and A, these patients can only make IgM.
Explain the abnormal % of antibodies in patients with hyper IgM syndrome
CD40 Ligand mutations
What are Microbial Factors that influence how we respond immunologically?
Microbial Factors
- Type of micro-organism (e.g. virus, bacterium, parasite).
- Amount/Dose (degree of exposure)
- Virulence of the organism
- Route of entry
What are the Host Factors that influence how we respond immunologically?
Host Factors
- Integrity of innate barriers
- e.g. skin and phagocytic pathways
- Adaptive immune competence.
- Genetic capacity (HLA, Ig and TCR genes) to respond normally to a specific organism.
- Evidence of previous exposure (natural or acquired).
- Existence of other infection.
What aspects of the pathogens and antigens is the immune system able to respond to?
Virus, Bacteria and Parasites
Viruses
- Lytic or integrated cycle
- Capsid antigens
- Internal structural components (HLA I)
- Metabolic products (HLA I)
Bacteria (and Fungi)
- Extracellular growth (e.g. s. aureus)
- Structural/surface components
- Metabolic products and toxins
- Intracellular growth(e.g. m. tuberculosis)
- Expressed via HLA I
Parasites
- Large (multicellular) (slower)
- Life cycle changes
- Radical changes in antigenicity
Specifically, how do Immune systems respond to bacteria/viruses? (7)
- Direct neutralization by antibodies
- Opsonization and phagocytosis
- Complement-mediated effects
- HLA-restricted T cell-mediated cytotoxicity
- NK cell-mediated cytotoxicity
- Inflammatory and immunoregulatory cytokines
- Antiviral cytokines
When are antibodies useful?
Antibodies
Effective against antigens outside cells
-
Virus particles
- (IgA, IgG, IgM)
-
Toxins
- (IgG, IgM)
-
Extracellular bacteria
- (IgA, IgM, IgG)
-
Parasites
- (IgE, IgA)
What are cytotoxic T cells effective against?
Cytotoxic T Cells
Effective against intracellular antigens
- Virus infections (cytoplasmic peptides)
- Tumour antigens
- Transplanted organs
Case
Start recurrent infections (mostly bacterial infections):
- Pneumonia
- Otitis media (inflammation of middle ear)
- Erysipelas (streptococcal skin infection)
Serum immunoglobulin tests (deficient in all antibodies):
- IgG: 8g/l (normal 60 - 150)
- IgA: 0 g/l (normal 5 - 12.5)
- IgM: 1g/l (normal 7.5 - 15)
Few detectable B cells and no tonsils.
What is a possible diagnosis?
Possible diagnosis is X-linked agammaglobulinaemia
Deficient in all anitbodies
Mostly bacterial infections (pneumonia, ottits media, erysipelas)
What is the first response to bacterial pathogens?
Pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), peptidoglycans trigger local inflammation:
- Vascular permeability changes
- Phagocyte recruitment
- Acute phase protein (APP) induction
- Local temperature change
This leads to phagocytosis and complement activation
How do we form immunity to bacteria?
Antibodies will be of value in bacterial and parasitic infections if they lead to the inactivation or destruction of these micro-organisms. Antibodies and complement provide immunity against bacteria:
- Prevent adherence or reduce mobility
- Enhance bacterial destruction (complement)
- Enhance phagocytosis (opsonisation)
How do Bacteria avoid antibody effects?
Bacteria have developed mechanism that are inherently r_esistant to antibody-mediated damage:_
- Capsule resists opsonisation (e.g. haemophilus influenzae)
- Intracellular growth (e.g. mycobacterium tuberculosis)
Where pathogen’s preferred site of infection is cytoplasm of a phagocytic cell (e.g. mycobacterial infections), antibodies may actually assist pathogen.
Describe Mucosal Immunity (antibodies at mucosal surfaces)
Adherence to _epithelial cells of mucus membrane_s is often essential for viral infection and bacterial colonization.
- IgA affords protection in external body fluids, tears, saliva, nasal secretions and those bathing surface of intestines and lungs.
- If an infectious agent succeeds in penetrating the IgA barrier, it comes up against IgE facet of secretory system.
- Although present in low concentration, IgE is bound very firmly to Fc receptors of mast cells, and contact with antigen.
This leads to release of mediators which effectively recruit agents of immune response and generate local acute inflammatory reactions
__________ will protect you,
when
_________ infect you
Lymphocytes
Parasites (+ bacteria)
Describe Natural KIller Cells
NK cells are generally l_arge granular leukocytes_ comprising 1-5% of mononuclear cells in blood (also spleen and peritoneal exudate).
It is identified by presence of Fcγ receptor (CD16), CD56, CD57 surface marker.
They don’t have rearranged immunoglobulin genes or TCR genes (not classical B or T cells)
- When they bind to cells that have down-regulated HLA I expression (via killer-inhibitory receptor), they are activated to kill those cells using mechanisms similar to those used by CD8 cytotoxic T cells.
- Targets with down-regulated HLA/MHC I expression are often virus-infected cells or tumour cells.
- Therefore, response early in viral infection and in cancer.
- Their activity can be enhanced by cytokines produced by helper T cells, e.g. interleukin 2 and interferon–γ (IL-2 and IFN- γ).
- They also use their Fc receptors (CD16) to bind antibodies attached to target cells (i.e. cytophilic antibodies) and exhibit antibody-dependent cell-mediate cytotoxicity (ADCC).
- Killer Inhibitor Receptor (KIR) binds HLA I
- There is no antigen priming required
Describe the what happens after Acute Viral Infection
The graph shows various host responses during the course of a typical acute viral infection. Note that recovery from such viral infections is strongly influenced by cytotoxic T cell activity and antiviral cytokine interferon rather than antibodies
1) Virus
2) Interferon
3) NK activity
4) Cytotoxic T cells
Describe the activity of the different types of Interferons
Interferons
Interferons are important antiviral proteins.
- IFNγ (sometimes referred to as type II interferon) is a product of CD4 T cells.
- IFNα and IFNβ (type I interferons) production and secretion are transiently induced in most cells of body when they are undergoing viral infection.
Interferons act on uninfected cells to induce a transient antiviral state by inducing specific enzymes in cell to cleave viral RNA.
Cytokines such as IL-2 and IFNγ can stimulate NK cell activity and up-regulate class I MHC expression on target cells to enhance lysis (killing) by NK and cytotoxic T cells. IFNγ can also activate intracellular killing of bacteria by macrophages.
