host defence in the lung 3

Question 1

innate vs adaptive immunity

Answer 1

• 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

Question 2

antigen

Answer 2

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

Question 3

cells of adaptive immune system

Answer 3

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

Question 4

T cells

Answer 4

• 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

Question 5

where are T and B cells generated ?

Answer 5

primary lymphoid tissue - bone marrow

Question 6

where are T and B cells activated?

Answer 6

secondary lymphoid tissue e.g. tonsils, thymus, spleen

Question 7

B cells

Answer 7

• 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

Question 8

properties of the adaptive immune system

Answer 8

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.

Question 9

How do lymphocytes recognize specific antigens?

Answer 9

• 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

Question 10

Diversity and specificity in adaptive immunity

Answer 10

• 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)

Question 11

How do we get millions of unique T and B cells?

Answer 11

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

Question 12

B cell and T cell receptors are slightly different

Answer 12

• 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)

Question 13

MHC molecule

Answer 13

• 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

Question 14

Immune tolerance

Answer 14

• 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

Question 15

Central tolerance

Answer 15

In the thymus or bone marrow, lymphocytes that react with self-antigens are deleted or develop into suppressor ‘Tregs’

Question 16

Peripheral tolerance

Answer 16

In lymph nodes, autoreactive clones escaping central tolerance are deleted or suppressed by Tregs

Question 17

Immunological memory

Answer 17

• 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

Question 18

recognition and killing of pathogens

Answer 18

• 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

Question 19

vaccination

Answer 19

• 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

Question 20

when it goes wrong

Answer 20

• 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

Question 21

failure of T cell immunity

Answer 21

• 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

Question 22

HIV and T-helper cells

Answer 22

• 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

Question 23

Failed tolerance (autoimmune disease)

Answer 23

• 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)

Question 24

What causes inflammation to be chronic?

Answer 24

1. Initiating cause persists
   Persistent infection – eg mycobacteria, abscess
   Persisting irritant eg smoking, gallstones
   Foreign bodies eg inhalation of food
2. cellular response is inappropriate
   autoimmunity eg rheumatoid arthritis
   granulomatous disease eg sarcoidosis
3. structural abnormalities
   bronchiectasis – local defences malfunction
   diverticular disease

Question 25

Patterns of chronic inflammation

Answer 25

• 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.

Question 26

Consequences of chronic inflammation

Answer 26

• 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

Question 27

Treatment of chronic inflammation

Answer 27

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