Respiratory Immunology 2 Flashcards
Stages of response to an infection?
Adherence to epithelium Local infection and epithelium penetration Local infection of tissues Lymphatic spread Adaptive immunity
Timescale of the acquired immune response?
After 96 hours
Organs involved with the adaptive immune response?
Thymus - in anterior mediastinum and where T cells mature Bone marrow Tonsils - specialised lymph nodes Spleen Appendix
Generation of T-lymphocytes?
Arise from haematopoetic stem cells in bone marrow
Form LYMPHOID PROGENITORS and then PRE T-CELLS
Pre T-cells exported to thymus where they undergo selection (only 10% cells survive)
Mature T-lymphocytes enter circulation and reside in lymph nodes and secondary lymphoid follicles
How many distinct T cell clones are there?
Each individual possesses 107-109 distinct T cell clones and each is ready to use when the right antigen comes along
T-lymphocyte functions?
Defense against INTRACELLULAR PATHOGENS and VIRUSES
Immunoregulation
Classification of T-lymphocytes?
Two main groups which have different functions and different expression of cell surface proteins:
CD4
CD8
Functions and mechanism of CD4+ T lymphocytes?
Recognise peptides presented on HLA class II molecules
Immunoregulatory functions:
Provide COSTIMULATORY signals - for ACTIVATION OF CD8+ T lymphocytes and NAIVE B CELLS and also INFLUENCE PHAGOCYTE FUNCTION
Produce cytokines
Regulate other lymphocytes and phagocytes
What does HIV do?
Knocks out CD4+ cells and thus affects CD8+ and B cells as well
What are CD8+ cells and mechanism of recognition?
Specialised CYTOTOXIC cells that recognise peptides in association with HLA class I (HLA-A, HLA-B, HLA-C)
Functions of CD8+ cells?
Important in defense against VIRAL INFECTIONS and TUMOURS
Kill cell directly via production of pore-forming molecules (PERFORIN); can also trigger apoptosis of the target and can secrete cytokines, like IFNγ
B lymphocyte generation and locations?
Arise from haematopoietic stem cells in bone marrow (do not have to go to thymus like T cells)
Mature B lymphocytes found mainly in BONE MARROW, LYMPHOID TISSUE and SPLEEN
Functions of B lymphocytes?
Antibody production Antigen presentation (showing pathogen to other immune system components)
Normal B lymphocyte development?
Stem cells form lymphoid progenitors which then form pro B and pre B cells
These can be used to form IgM B cells
IgM B cells get signals, and can mature into different immunoglobulins producing B cells:
IgG
IgE
IgA
IgM plasma cells
Activation of T lymphocytes and what this involves?
Encounters with antigen in lymph node
Provided with appropriate signals from CD4+ cells - stimulated B cells rapidly proliferate
Undergo complex genetic rearrangements - B cells become more specific
Further differentiation produces:
Long-lived memory cells
Plasma cells which produce antibodies
Antibody functions?
Important in defense against BACTERIA
Identify pathogens
Recruit other components of immune response to remove pathogens, like complement, phagocytes, NK cells
Neutralisation of toxins
Defects of the adaptive immune response?
Defects of haematopoietic stem cells - Recticular dysgenesis
Failure of lymphocyte precursors - Severe Combined Immunodeficiency
Failure of thymus development - DiGeorge Syndrome
Defective T lymphocyte activation and effector function:
Failure of HLA molecule expression - Bare Lymphocyte Syndromes
Failure of signalling, cytokine production and effector functions - gIFN and/or IL12 deficiency
Failure of normal apoptosis - Autoimmune Lymphoproliferative Syndromes
Recticular dysgenesis?
Failure of production of: Neutrophils Lymphocytes Monocyte/macrophages Platelets Fatal unless corrected with bone marrow transplant
Thymus in recricular dysgenesis?
Small thymus as these children have no lymphocytes
What is severe combined immunodeficiency?
AKA SCID
Failure of lymphocyte production (defect in lymphocyte precursors)
Adults can get this
Clinical phenotype of SCID?
Unwell by 3 months of age
Failure to thrive
Infections of ALL TYPES (common infections being more severe than usual, unusual and opportunistic infections and vaccine associated disease -live)
Unusual skin disease - Graft vs Host disease (maternal lymphocytes not killed by child’s so they colonise “empty” bone marrow and attack baby’s own cells causing severe eczema like problem)
Family history of early infant death
Why is the baby usually well in SCID until 3 months?
Maternal IgG protects the neonate (via placenta and breast milk)
SCID causes?
Over 20 possible pathways, e.g:
Deficiency of cytokine receptors, signalling molecules, metabolic defects and defective receptor rearrangements
Describe the commonest form of SCID?
X-linked SCID - mutation of component of IL2 receptor (drives lymphocyte proliferation); shared by many other cytokine receptors and results in inability to respond to cytokines:
Failure of T and NK cell development
Production of immature B cells
Clinical phenotype of X-linked SCID?
Very low/absent T cells (as IL2 is important for T cell development)
Normal/increased B cells but are immature
Poorly developed lymphoid tissue and thymus
SCID treatment?
Prphylactic treatment with antibiotics/anitfungals and no vaccines
Antibody replacement with iv immunoglobulin
Definitive treatment with a stem cell transplant from HLA identical sibling, if possible
SCID gene therapy?
Lymphoid cells are dysfunction so stem cells can be treated ex vivo to express missing component (IL2 receptors)
RISK OF CANCER
What is DiGeorge syndrome and cause?
Developmental defect of the 3rd/4th pharyngeal pouch (strange from mid-face to below the aortic arch), due to deletion of chromosome 22q11 (key gene probably TBX1)
Appearance and clinical features of child with DiGeorge syndrome?
T cell lymphoenia (low levels) - FAILURE OF THYMIC DEVELOPMENT results in immunodeficiency of T cells as there is no place for T cells to mature
Developmental delay
Psychiatric disorders - OCD, schizophrenia
Low set ears that are abnormally folded
High forehead
Cleft palate
Small mouth and jaw
Hypocalcaemia - do not have parathyroids which are important for calcium metabolism and they will suffer from seizures
Oesophageal atresia - oesophagus ends in a blind-ended pouch instead of connecting to stomach
Complex congenital heart disease
Infections in people with DiGeorge Syndrome?
RECURRENT VIRAL INFECTIONS - CD8 T cells essential in killing if viral infected T cells
RECURRENT BACTERIAL INFECTIONS - CD4 T cells help B cells make antibody
FREQUENT FUNGAL INFECTIONS - T cells essential for fungal defense
Lab investigation for DiGeorge syndrome?
Absent/decrease no . of T cells, due to defective T cell activation response
Normal/increased B cells that produce low IgA, IgG and IgE; so, poor antibody response to specific pathogens
Normal NK cell numbers
Managing DiGeorge syndrome?
Correct metabolic/cardiac abnormalities
Prophylactic antibiotics
Early, aggressive infection treatment
Patient may require immunoglobulin replacement
DiGeorge Syndrome with increasing age?
T cell function improves with age as T cells may have found another place to mature
Disorders of T cell effector functions?
Cytokine production
Cytotoxicity
T-B cell communication
Describe defense against intracellular organisms
E.g: mycobacteria
IL12-gIFN network activated:
Infected macrophages stimulated to produce IL12
Induces T cells to secrete gIFN
gIFN feeds back to macrophages and neutrophils
Stimulates TNF production
Activates NADPH oxidase
What results in defective cytokine production in T cell effector function?
IL12
IL12 receptor
gIFN
gIFN receptor
Infections in people who have defective cytokine production?
TB
Atypical mycobacteria
BCG infection after immunisation
Deep fungal infections, e.g: Aspergillus
Clinical features of T cell deficiencies?
Recurrent infections: Viral Fungal Bacterial Intracellular pathogens, e.g: mycobacteria
Opportunistic infections
Malignancies at young age
Autoimmune disease
First line investigations for T cell deficiencies?
Total wbc count (normally higher in children than in adults) and differential
Serum immunoglobulins (surrogate marker of functional T cells) and protein electrophoresis
Quantification of lymphocyte sub-populations
Second line investigations for T cell deficiencies?
Functional tests of T cell activation and proliferation - useful is signalling/activation defects are suspected
Additional tests of lymphocyte lineage
HIV TEST IS ESSENTIAL
Clinical presentation of antibody deficiencies?
RECURRENT BACTERIAL INFECTIONS (viral less common)
ANTIBODY MEDIATED AUTOIMMUNE DISEASE:
Idiopathic thrombocytopaenia - low platelet levels
Autoimmune haemolytic anaemia - autoantibodies attack rbcs
B cell maturation defects?
Failure of lymphocyte precursore - severe combined immune deficiency
Failure of B cell maturation - Bruton’s X-linked hypogammaglobulinaemia
Failure of IgA production - Selective IgA deficiency
Failure of IgG production: Common variable immune deficiency
Selective antibody deficiency
What is Bruton’s X-linked hypogammaglobulinaemia?
Failure to produce mature B cells:
No circulating B cells
No plasma cells
No circulating antibody after first 6 months
Describe selective IgA deficiency
2/3rd individuals asymptomatic
1/3rd have recurrent respiratory tract infections
Genetic component but cause is unknown
What is common variable immune deficiency?
Heterogenous group of disorders of which the cause and disease mechanism are unknown
Common variable immune deficiency and consequences?
Cause and mechanism unknown:
Low IgG, IgA, IgE
Recurrent bacterial infections - often severe end-organ damage, e.g: bronchiectasis, persistent sinusitis, recurrent GI infection
Often associated with autoimmune disease
Granulomatous disease
First line investigations for B cell deficiencies?
Total wbc count and differential
Serum immunoglobuline
Serum and urine electrophoresis
Second line investigations for B cell deficiencies?
Quantification of B and T lymphocytes
Specific antibody responses to known pathogens:
Measure IgG antibodies against tetanus, Haemophilus influenzae B and S. pneumoniae
If specific antibody levels low, immunise with appropriate KILLED VACCINE and repeat antibody measurement 6-8 weeks later
Failure to mount a response indicates a significant defect in antibody production
Managing B cell deficiencies?
Aggressive infection treatment
Immunoglobulin replacement - derived from polled plasma of 1000s of donors and contain IgG antibodies to a wide variety of common organisms; usually administered via iv every 3-4 weeks to maintain IgG levels within normal range and so is life long
Stem cell transplantation in some situations
Summary of selective IgA deficiency diagnosis?
Serum immunoglobulins: IgM - normal IgG - often increased IgA - none IgE - normal
Lymphocyte subpopulations:
B cells - normal
T cells -normal
Summary of common variable immune deficiency diagnosis?
Serum immunoglobulins: IgM - normal but decreased IgG - decreased IgA - decreased IgE - decreased
Lymphocyte subpopulations:
B cells - variable
T cells - variable
Other investigations:
Failure to produce specific antibodies after test immunisation
Summary of specific antibody deficiency diagnosis?
Serum immunoglobulins: IgM - normal IgG - normal IgA - normal but decreased IgE - normal
Lymphocyte subpopulations:
B cells - normal
T cells - normal
Other investigations:
Failure to produce specific antibodies after test immunisation
