host defence in the lung 3 Flashcards
1
Q
innate vs adaptive immunity
A
- Two systems intimately closely interrelated
- Initial responses to pathogens often innate
- Adaptive responses are later, pathogen and antigen-specific and generate ‘memory’ with a learned response that is more rapid and effective
2
Q
antigen
A
Molecule capable of inducing a specific immune response on the part of the host organism. Can be proteins, polysaccharide, lipids, DNA etc; soluble or part of a cell or pathogen
3
Q
cells of adaptive immune system
A
antigen presenting cells (innate/adaptive interface) - taste the environment, phagocytose foreign material, process and present antigen in lymphoid tissue
Lymphocytes (adaptive effector cells) - T cells , B cells
4
Q
T cells
A
- Cytotoxic T cells (Tc) express the surface molecule CD8. When activated they kill tumour and virus-infected cells that express the activating antigen
- T helper (Th) cells express CD4.When activated they orchestrate the immune response by cytokine production. Different subsets of Th cells have different helper functions eg activating innate immune cells, assisting B cells to make antibodies.
- T regulatory (Treg) cells suppress autoreactive lymphocytes to prevent them from attacking our own antigens.
- Memory T cells enable enhanced future responses to the same antigen
5
Q
where are T and B cells generated ?
A
primary lymphoid tissue - bone marrow
6
Q
where are T and B cells activated?
A
secondary lymphoid tissue e.g. tonsils, thymus, spleen
7
Q
B cells
A
- The unique B cell receptor is an immobilised antibody
- When activated by specific antigen a B cell becomes a plasma cell which exists (for days) to make antibodies that bind the antigen
- Each antibody recognises a specific epitope (part of an antigen)
- Antibodies have a number of actions eg helping innate cells to ‘eat’ bacteria
- Memory B cells allow rapid and augmented response to subsequent infection
8
Q
properties of the adaptive immune system
A
Ability to mount specific responses to a huge range of pathogen-derived antigens (diversity)
• Avoids reacting to “self” antigens (self-tolerance)
• Development of immunological memory, with each pathogen ‘remembered’ by long-lived memory B and T cells. Enables a more rapid and effective second response.
9
Q
How do lymphocytes recognize specific antigens?
A
- T cells and B cells express different unique antigen receptors (the B cell receptor and the T cell receptor)
- The variable region determines the receptor specificity, binding to antigen like a lock and key
- Estimated to be approx. 1018 different antigen receptors
10
Q
Diversity and specificity in adaptive immunity
A
- Generation of pathogen-specific variable regions in lymphocyte receptors is the basis of diversity and specificity
- Much diversity is generated early in development via DNA rearrangements (VDJ recombination)
- Exposure to relevant antigen triggers replication with errors in variable region DNA replication generating further diversity (somatic hyper-mutation)
- Selection for higher affinity clones (affinity maturation)
11
Q
How do we get millions of unique T and B cells?
A
Random recombination events occur between about 50 Variable (V) 27 Diversity (D) and 6 Joining (J) segments in both heavy and light chains
Recombination is not precise (nucleotides inserted or deleted) greatly increasing diversity
12
Q
B cell and T cell receptors are slightly different
A
- B-cell receptors recognize antigen in native form (as they exist in nature) as well as presented antigen.
- B cells may receive help from T cells. This enables them to respond to certain antigens more effectively
- T-cell receptors can only recognise antigens that have been broken down and presented by an MHC (major histocompatibility complex) protein by an antigen presenting cell (APC)
13
Q
MHC molecule
A
- MHC stands for Major Histocompatibility Complex, a series of cell surface proteins found on immune and non-immune cells that are essential for T cells to recognise antigens
- MHC (HLA) molecules vary between individuals and in the setting of organ transplants they are highly immunogenic (HLA mis-matching leads to transplant rejection)
- MHC class 1 molecules are expressed on all nucleated cells and enable cytotoxic T cells to recognise and kill viral-infected cells
- MHC class 2 molecules are expressed by antigen presenting cells and are co-expressed with antigen to enable the activation of helper T cells
14
Q
Immune tolerance
A
- A state of unresponsiveness of the immune system to antigens that normally have the capacity to elicit an adaptive immune response
- Tolerance can be to self, but also to the fetus in pregnancy, or it can develop to pathogens (chronic infections) or cancers
- Failure to establish self-tolerance leads to autoimmune disease, where our immune system attacks our own antigens. Examples include rheumatoid arthritis and , systemic lupus erythematosus
- Self-tolerance arises both centrally and peripherally
15
Q
Central tolerance
A
In the thymus or bone marrow, lymphocytes that react with self-antigens are deleted or develop into suppressor ‘Tregs’
16
Q
Peripheral tolerance
A
In lymph nodes, autoreactive clones escaping central tolerance are deleted or suppressed by Tregs
17
Q
Immunological memory
A
- Allows rapid immunological response on subsequent exposure
- Following activation a small proportion of high affinity B and T cells differentiate into long-lived memory cells, residing in lymph nodes or tissues
- Memory cells are distinguished from naïve cells by high affinity receptors, increased lifespan, and faster and stronger response to stimulation
18
Q
recognition and killing of pathogens
A
- Activated cytotoxic T cells (CD8 +ve) kill virus-infected or tumour cells
- Activated helper T cells (CD4 +ve) produce cytokines to orchestrate immune response and ‘help’ other cells. Many subsets with different helper functions
- Activated B cells become plasma cells and produce specific antibodies to kill or limit pathogens and help innate immune cells eat them
19
Q
vaccination
A
- Vaccination harnesses immunological memory to enhance adaptive immunologic responses to pathogens
- Vaccines are derived from pathogens (eg dead or attenuated bacteria, capsular polysaccharide, viral proteins)
- Vaccines can prevent infection or reduce morbidity in individuals, and also generate ‘herd immunity’
- Booster doses better harness immunological memory and generate high affinity antibodies
20
Q
when it goes wrong
A
- Failure of antibody production leads to recurrent or severe bacterial infections
- Failure of T cell function leads to ‘opportunistic’ infections such as fungi and viruses, and tumours
- Failure of tolerance leads to autoimmune disease
- Failure to eliminate pathogens (and autoimmune disease) leads to chronic inflammation
21
Q
failure of T cell immunity
A
- Primary (rare immunodeficiencies) or secondary (immunosuppressive drugs, HIV infection)
- Typical and ‘opportunisitic’ infections (which do not cause disease in healthy individuals)
- Fungi (pneumocystis, aspergillus, cryptococcus)
- Viruses – disseminated CMV or EBV
- Bacteria eg pneumonia and TB
- Parasites eg toxoplasma, cryptosporidia
- Increase in some malignancies
22
Q
HIV and T-helper cells
A
- Acquired immune deficiency syndrome (AIDS) is caused by HIV, a retrovirus spread by bodily fluids
- HIV infects CD4+ (T helper) cells
- Untreated CD4+ levels progressively decline leading to AIDS, a failure of cell-mediated immunity
- Highly active anti-retroviral therapy (HAART) reduces viral burden and maintains the immune system for years but globally HIV-related lung disease remains a major cause of death
23
Q
Failed tolerance (autoimmune disease)
A
- Failure of immunological tolerance to “self”
- Most autoimmunity occurs later in life due to failure of peripheral tolerance; initiating events are often unclear
- Genetic associations (with MHC), commoner in women
- Clonal proliferation of autoreactive lymphocytes with target-specific tissue destruction (or activation)
- Examples include rheumatoid arthritis (anti-citrullinated proteins), Graves disease (anti-TRH receptor), vasculitis (anti-neutrophil)
24
Q
What causes inflammation to be chronic?
A
- Initiating cause persists
Persistent infection – eg mycobacteria, abscess
Persisting irritant eg smoking, gallstones
Foreign bodies eg inhalation of food - cellular response is inappropriate
autoimmunity eg rheumatoid arthritis
granulomatous disease eg sarcoidosis - structural abnormalities
bronchiectasis – local defences malfunction
diverticular disease
25
Patterns of chronic inflammation
* Chronic suppurative inflammation – mostly innate cells (neutrophils) often surrounded by a capsule of chronic inflammatory cells or fibrous tissue
* Chronic autoimmune inflammation (mostly cells of adaptive immune system). May lead to fibrosis
* Chronic granulomatous inflammation (mostly cells of adaptive immune system). May lead to fibrosis.
26
Consequences of chronic inflammation
* Systemic – malaise, weight loss, fever, sweats, anaemia
* Tissue Destruction – eg cavity formation
* Fibrosis – eg strictures, organ dysfunction
* Growth disorders – metaplasia, neoplasia e.g. carcinoma of bronchus in pulmonary fibrosis
27
Treatment of chronic inflammation
Cause-specific treatments first, if available (e.g. treatment of chronic infection, surgical procedures to removal of foreign material)
Anti-inflammatory treatment NSAIDs, steroids
Immunsuppression – can target specific cell types (eg T cells or B cells) or specific cytokines. Consequences include increased infection
