Primary Immunodeficiency disorders (PID) (pie for finals) Flashcards
Outline the immune defences of the respiratory tract prior to the alveoli
- Large particles are deposited in the nasopharynx and tonsillar regions and cleared by inertial forces (coughing and sneezing).
- Further down the respiratory tract foreign particles are captured on the mucociliary surface and propelled back on an “escalator” to the upper airways from where they are expelled.
- Various antimicrobial compounds also exist within this mucous layer including collectins such as surfactant proteins, LBP (a protein that binds to bacterial lipopolysaccharide [LPS] allowing it to be recognised by innate immune cells) and complement components that, amongst other effects, bind to bacterial cell walls allowing their uptake by immune cells.
- Antimicrobial peptides are also secreted into this environment.
Describe the immune defence in the alveoli
Alveoli only house a small number of immune cells. The primary one being alveolar macrophages
What is the function of alveolar macrophages in the alveoli of the lungs ?
- These macrophages secrete a plethora of anti-microbials including oxygen metabolites, lysozyme, antimicrobial peptides and proteases.
- They also phagocytose and kill microbes. Alveolar macrophages are important for the recruitment of other immune cells when the threat is great by secretion of cytokines (interleukins-1, -6, and tumor necrosis factor) and chemokines (including interleukin-8, that recruits neutrophils).
- They can also process and present antigens to helper and cytotoxic T cells.
What additional immune cells are found in the lungs besides alveolar macrophages ?
- Dendritic cells are known to project their dendrites into the airway lumen.
- T cells (predominantly cytotoxic) exist between epithelial cells (intraepithelial lymphocytes [IELs]).
- Some CD4+ helper T cells are found between the airspaces as are collections of B lymphocytes organised into follicles known as inducible bronchus associated lymphoid tissue (iBALT).
- Some neutrophils and rare mast cells may also be present
Note though most cells arrive when they are needed.
Go over this
Describe the immune response to wounded tissue
- Damaged tissue cells release small molecules that act as ‘danger signals’ & activate tissue-resident mast cells
- The mast cells in turn degranulate releasing vasoactive inflammatory mediators such as histamine (this inflam response is initiated within mins)
- Post-capillary venules in the local area dilate; the endothelial cell layer becomes permeable; and the endothelial cells themselves increase expression of cell surface adhesion molecules
- Clotting factors enter the wounded tissue and start to form a clot at the wound site
- Neutrophils respond to the inflammatory mediators and enter the wounded tissue site via the process of transendothelial migration
- Intracellular and/or extracellular pathogens may then enter the wounded tissue
Describe the innate immune response to infection of a wounded tissue caused by extracellular pathogens
- Tissue-resident macrophages and mast cells as well as newly recruited neutrophils recognise extracellular pathogens via PAMP:PRR interactions
- These leukocytes then become activated and start to kill the invading pathogens
- Debris from dead/dying pathogens (containing PAMPs and/or antigens) are taken up by tissue resident Dendritic cells (via phagocytosis)
- Phagocytosed pathogenic material is processed (degraded) and peptide antigens are loaded onto MHC-I and MHC-II molecules before being displayed on the surface of the Dendritic cell.
- While this is happening TNFα, chemokines and other pro-inflammatory cytokines are being produced by activated neutrophils and macrophages.
- These pro-inflammatory mediators serve to re-enforce acute inflammatory responses in the local vasculature.
- TNFα also serves to activate Dendritic cells which in turn start to express co-stimulatory molecules on their surface.
- Pro-inflammatory cytokines produced within the infected tissue also have systemic effects
- Acute phase proteins migrate into infected tissues
- Activated Dendritic cells leave the infected, wounded tissue and migrate via the lymphatic system to local draining lymph nodes.
- Similarly, opsonised pathogenic debris/antigens are directly transported to the lymph nodes via the lymphatic system.
How do the leucoytes involved in the innate immune response to infected wounded tissue start to kill the invading pathogens?
- Degranulate ==> release of toxic enzymes/molecules (neutrophils only)
- NETocysis (neutrophils only)
- Phagocytosis and lysosomal killing (ROS-dependent or independent) – macrophages and neutrophils
What are the additional systemic effects of the pro-inflammatory cytokines produced within infected tissues by activated neutrophils & macrophages during the innate immune response ?
- Hypothalamus stimulated ==> fever
- Bone marrow stimulated ==> increased neutrophil/monocyte production (leucocytosis)
- Liver stimulated ==> Acute Phase Response ==> Increased CRP, MBL & C3
What acute phase proteins migrate into infected tissues during the innate immune response to infected wounded tissues?
- Pathogen opsonisation (CRP)
- Complement System activation (MBL, C3) ==> Opsonisation, MAC formation & Acute inflammation
Describe the innate immune response to infection with intracellular pathogens causing infected wounded tissue
- At steady-state normal tissue cells inhibit Natural Killer (NK) cells via MHC-I/self-peptide expression.
- Infection with intracellular pathogens such as viruses results in the production of anti-viral cytokines such as IFNα/β by the infected cells.
- In an attempt to evade the adaptive immune system, many intracellular pathogens downregulate expression of MHC-I on the surface of the infected cell.
- Any remaining MHC-I present will display either tissue (self) peptides or viral peptides
- In the absence of MHC-I surface expression, Natural Killer cells will activate, degranulate and kill the infected tissue cells ==> Perforin + granzymes à Apoptosis
Describe the adaptive Immune Responses to Extracellular and Intracellular Pathogens
- Dendritic cells migrate into local draining lymph nodes and move into the T cell zone
- Opsonised antigens are trapped by ‘stromal’ cells within the B-cell follicles of the lymph node
- Antigen-specific T cells and B cells migrate into lymph nodes from the vasculature (via transendothelial migration) and home to specific ‘addresses’ within the lymph node (T cell zones and B cell follicles)
- If antigen-specific CD4+ T cells encounter the correct peptide (presented by MHC-II) on the Dendritic cells plus a second, co-stimulatory signal, they will become activated.
- Activated CD4+ T cell secrete the T cell growth factor Interleukin 2 (IL-2) and start to proliferate.
- Activated CD4+ TH0 cells secrete more IL-2 which further enhances proliferation and differentiation of activated CD4+ T cells but also that of antigen-activated CD8+ T cells
- Some effector T cells (TH1 cells; CTLs) migrate out of the lymph node and enter infected inflamed tissues (via transendothelial migration)
- Back in the infected tissue, macrophages start to process and present pathogen-derived peptides on their surface in complex with MHC-II (and MHC-I)
- In infected tissues, antigen-specific TH1 cells can be re-activated by macrophages (via peptide/MHC-II)
- Re-activated TH1 cells express co-stimulatory molecules and cytokines that turn macrophages into ‘superkillers’ (via á production of lysosomal ROS/RNS)
- CD8+ Cytotoxic T lymphocytes (CTLs) can be re-activated by viral peptide/MHC-I on infected tissue cells, resulting in their death (perforin + granzyme à apoptosis)
- Back in the lymph node, antigen-specific B cells can bind to opsonised pathogen-derived antigens (in an antigen-specific manner). They can internalise the bound antigen and display peptides from this on their surface, in complex with MHC-II
- Antigen-specific TFH cells migrate into the B cell follicle where they can be re-activated by antigen-experienced B cells (via peptide/MHC-II)
- Reactivated TFH cells express co-stimulatory molecules and cytokines that induce proliferation and differentiation of the B cell (the Germinal Centre reaction)
- Antigen-specific antibodies can circulate through out the body helping to kill and eliminate invading pathogens (opsonisation, neutralisation, complement activation etc)
What are the different ways immunodeficiencys can develop?
- They can be inherited
- Acquired through infection
- Or produced unintentionally by drugs such as those used to treat people with cancer or those who have received transplants.
What are the hallmarks of immunodeficiency ?
Think ‘SPUR’
- Serious infections - Unresponsive to oral antibiotics
- Persistent infections - early structural damage, chronic infections
- Unusual infections - unusual organisms & unusual sites
- Recurrent infections - two major or one major and recurrent minor infections in one year
What additional features are suggestive of someone potentially having immunodeficiency ?
- Weight loss or failure to thrive
- Severe skin rash (eczema)
- Chronic diarrhoea
- Mouth ulceration
- Unusual autoimmune disease
- Lymphoproliferative disorders
- Cancer
- Family history
List some of the types of infection/organisms someone with an immunodeficiency is susceptable to
- Common bacteria: eg Staphylococcus Aureus
- Unusual bacteria: eg Burkholderia cepacia
- Mycobacteria: both tuberculosis and atypical mycobacteria
- Fungi - Candida, Aspergillus
Define what a primary immunodeficiency is vs a secondary immunodeficiency
Primary immunodeficiencies are the result of genetic defects, and secondary immunodeficiencies are caused by environmental factors, such as HIV/AIDS or malnutrition.
Secondary immunodeficiency’s are common and involve more than one component of the immune system
Primary immunodeficiency’s are rare and are classified based on the component of the immune system they affect e.g. B cell disorders etc
What is the main initial manifestation in most cases of primary immunodeficiency disorders (PIDs) and what are the main complications?
- Initial manifestation = Respiratory diseases
- Pulmonary complications
What are some of the upper and lower respiratory complications of PIDs?
Upper:
- Sinusitis
- Ottitis media
- Layrngeal oedema
It is reported that 10%-54% of patients with chronic sinusitis have PID, what is the most frequent PIDs associated with sinusitis and otitis media?
Primary antibody deficiency (PAD):
- Selective IgA deficiency
- Common variable immunodeficiency (CVID)
- Specific antibody deficiency (SAD)
- X-linked agammaglobulinemia (XLA)
What complement system disorder should be considered in patients with laryngeal oedema ?
Hereditary angioedema (HAE)
What defect causes hereditary angioedema ?
Low C1 inhibitor (C1-INH) protein levels
