Immunology Flashcards
skin - barriers to infection
- consists of tightly packed keratinised cells
- this physically limits colonisation by microorganisms
- low pH
- low oxygen tension
- sebaceous glands: hydrophobic oils that repel water & microorganisms, lysozymes that destroy the structural integrity of the bacterial cell wall, ammonia & defensins that have antibacterial properties
mucosal surfaces - barriers to infection
- mucus is a physical barrier that traps invading pathogens
- contains secretory IgA which binds to pathogens and prevents bacteria and viruses from attaching to and penetrating epithelial cells
- lysozyme and antimicrobial peptides directly kill invading pathogens
- lactoferrin starves invading bacteria of iron
- cilia directly trap pathogens and contribute to the removal of mucous, which is assisted by physical manoeuvres such as sneezing and coughing
benefits of commensal bacteria
- they compete with pathogenic bacteria for scarce resources
- they produce fatty acids and bactericidins that inhibit the growth of many pathogens
components of the innate immune system
cells
- polymorphonuclear cells (neutrophils, eosinophils, basophils)
- monocytes and macrophages
- NK cells
- dendritic cells
soluble components
- complement
- acute phase proteins
- cytokines and chemokines
key features of cells of the innate immune system
- essentially identical responses in ALL individuals
- cells express receptors that allow them to detect and home to sites of infection
- cells express genetically encoded receptors (PRRs) that allow them to detect pathogens at the site of infection
- cell has phagocytic capacity that allows them to engulf pathogens
- cells secrete cytokines and chemokines that regulate the immune response
polymorphonuclear cells
- produced in bone marrow
- migrate rapidly to site of injury
- express receptors for cytokines/chemokines - to detect inflammation
- express pattern recognition receptors - to detect pathogens
- express Fc receptors for Ig - to detect immune complexes
- capable of phagocytosis/oxidative & non-oxidative killing - particularly neutrophils
- release enzymes, histamine, lipid mediators of inflammation from granules
- secrete cytokines and chemokines to regulate inflammation
relationship between monocytes and macrophages
monocytes are produced in the bone marrow, circulate in the blood and migrate to tissues where they differentiate into macrophages
macrophages
- present within tissue
- express receptors for cytokines and chemokines - to detect inflammation
- express pattern recognition receptors - to detect pathogens
- express Fc receptors for Ig - to detect immune complexes
- capable of phagocytosis / oxidative and non-oxidative killing
- secrete cytokines and chemokines to regulate inflammation
- capable of presenting processed antigen to T cells
how are macrophages different to polymorphonuclear cells?
they can process antigens and present it to T cells
phagocyte recruitment
- cellular damage and bacterial products trigger the local production of inflammatory mediators (cytokines and chemokines)
- cytokines will activate the vascular endothelium enhancing permeability
- chemokines attract phagocytes (NB: macrophages are already present at peripheral sites)
recognition of microorganisms
- pattern recognition receptors (PRRs) like Toll-like receptors and mannose receptors recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA and RNA
- Fc receptors on these cells allows them to bind to the Fc portion of immunoglobulins thereby allowing the phagocytes to recognise immune complexes
what is opsonisation? what does it facilitate?
it facilitates endocytosis
- opsonins act as a bridge between the pathogen and the phagocyte receptor
- the antibodies will bind to Fc receptors on the phagocytes
- complement components can bind to complement receptors (e.g., CR1)
- acute phase proteins (e.g, CRP) will also promote phagocytosis
formation of phagolysosome
- the pathogen is taken up into a phagosome
- the phagosome will fuse with a lysosome to form a phagolysosome
- this is procted comparment in which killing of the organism occurs
- the killing of the pathogen can occur by oxidative mechanisms or non-oxidative mechanisms
non-oxidative killing within the phagolysosome
- killing by the release of bacteriocidal enzymes such as lactoferrin and lysozyme into the phagolysosome
- enzymes are present in granules
- each has a unique antimicrobial spectrum
- this results in a broad range of cover against bacteria and fungi
death of the phagocyte - neutrophils
- the process of phagocytosis depleted glycogen reserves within the neutrophil, which is then followed by neutrophil death
- as the cells die, residual enzymes are released which causes liquefaction of the adjacent tissue
- accumulation of dead and dying neutrophils within the infected tissue results in the formation of pus
- an accumulation of pus forms an abscess
summary of innate response to infection
- expression of endothelial activation markers
- mobilisation of phagocytes and precursors from bone marrow or within tissues
- increased neutrophil adhesion and migration into tissues
- macrophage - T cell communication
- phagocytosis of organisms
- oxidative and non-oxidative killing
- cell death and formation of pus
natural killer cells
- these are a type of lymphocyte
- present within the blood and may migrate to inflamed tissue
- express inhibitory receptors for self HLA which prevents inappropriate activation by normal self cells
- express a range of activatory receptors including natural cytotoxicity receptors that recognise heparan sulphate proteoglycans
- integrate signals from inhibitory and activatory receptors (usually the inhibitory signals will dominate)
- they are cytotoxic - kill ‘altered self’ cells (i.e., malignancy or virus-infected cells)
- secrete cytokines to regulate inflammation and promote dendritic cell function
dendritic cells
- reside in peripheral tissues
- express receptors for cytokines and chemokines (to detect inflammation)
- express pathogen recognition receptors (to detect pathogens)
- express Fc receptors for immunoglobulin (to detect immune complexes)
- capable of phagocytosis
following phagocytosis, dendritic cells will:
a. upregulate expression of HLA molecules
b. express co-stimulatory molecules
c. migrate via lymphatics to lymph nodes (mediated by CCR7) - present processed antigen to T cells in lymph nodes to prime the adaptive immune system
- express cytokines to regulate the immune response
adaptive immune system: components
humoral immunity
- B lymphocytes and antibody
cellular immunity
- T lymphocytes (CD4+ and CD8+)
soluble components
- cytokines and chemokines
what are primary lymphoid organs?
= organs involved in lymphocyte development
Bone marrow
- both T and B lymphocytes are derived from haematopoietic stem cells in the bone marrow
- it is the site of B cell maturation
Thymus
- site of T cell maturation
- most activate in the foetal and neonatal period, involutes after puberty
what are secondary lymphoid organs?
= anatomical sites of interaction between naive lymphocytes and microorganisms
examples:
- spleen
- lymph nodes
- MALT
key features of cells of the adaptive immune response
- wide repertoire of antigen receptors
- exquisite specificity
- clonal expansion
- immunological memory
T lymphocyte maturation
- arise from haematopoietic stem cells in the bone marrow
- exported as immature cells to the thymus where undergo selection
- mature T lymphocytes enter the circulation and reside in secondary lymphoid organs
- they undergo positive and negative selection before being exported to the periphery
- CD4+ recognises peptides presented by HLA class II
- CD8+ recognises peptides presented by HLA class I
CD4+ T cells (Helper T cells)
- recognises peptides derived from extracellular proteins
- these peptides are usually presented on HLA Class II molecules (HLA-DR, HLA-DP, HLA-DQ)
- they have important immunoregulatory functions of a full B cell response:
a. they provide help for the development of a full B cell response
b. they provide help for the development of some CD8+ T cell responses - different cytokines promote development along different lines of development
CD8+ cytotoxic T cells
- specialised cytotoxic cells
- recognise peptides derived from intracellular proteins presented on HLA class I (HLA-A, HLA-B and HLA-C)
- kills cells directly:
a. perforin (pore-forming) and granzymes
b. expression of Fas ligand - secrete cytokines (e.g., IFN-gamma, TNF-alpha)
- particularly important in defence against viral infections and tumours
T cell memory
- response to successive exposures of antigen is qualitatively and quantitatively different from that of first exposure
- there is a pool of memory T cells that are ready to respond to antigen
- these cells are more easily activated than naive cells
B lymphocyte maturation
they initially exist in the periphery as IgM B cells, but they can undergo a germinal centre reaction to differentiate into plasma cells expressing IgG, IgE and IgA
central tolerance
if the receptors on the B cells in the bone marrow recognise self, they will be deleted
if not, they will survive
antigen encounter by B cells - early IgM response
if the B cell in the periphery engages an antigen you can get an early IgM response where the cell differentiates into an IgM secreting plasma cell
antigen encounter by B cells - germinal centre reaction
- this is dependent on T helper cells
- firstly, dendritic cells will prime the CD4+ T helper cells
- the CD4+ cells then provide help for B cell differentiation
- this interaction is mediated by CD40L:CD40
- with the help of CD4+ cells, the B cells will proliferate
- they then undergo somatic hypermutation and isotype switching (from IgM to IgG/A/E)
- they will then become plasma cells which produce antibodies
what are immunoglobulins?
- soluble proteins made up of 2 heavy chains and 2 light chains
- heavy chain determines the antibody class (GAMED)
- they are subclasses of IgG and IgA
- antigen is recognised by the antigen binding region (Fab) which is made up of both the heavy and light chains
- effector function is determined by the constant region (Fc) of the heavy chain
function of antibodies
identification of pathogens and toxins (Fab-mediated)
interact with other components of immune responses to remove pathogens (Fc-mediated):
- complement
- phagocytes
- NK cells
particularly important in defence against BACTERIA of all kinds
what is complement?
20+ tightly regulated, linked proteins
- produced by the liver
- present in the circulation as inactive molecules
when triggered, they will enzymatically activate other proteins in a biological cascade
- results in a rapid, highly amplified response
which are the 3 pathways of complement activation?
- classical
- mannose binding lectin pathway
- alternative pathway
complement activation - classical pathway
- activated by immune complexes
- the formation of antibody-antigen immune complexes results in a conformational change in antibody shape which exposes the binding site for C1
- binding of C1 to the antibody results in activation of the cascade
- as it involves antibodies, it does depend on the activation of the adaptive immune response (i.e., it will NOT occur very early in the immune response)
complement activation - mannose binding lectin (MBL) pathway
- activated by the direct binding of MBL to microbial cell surface carbohydrates
- this directly stimulates the classical pathway involving C4 and C2 (but NOT C1)
- this is NOT dependent on the adaptive immune response
complement activation - alternative pathway
this is directly triggered by binding of C3 to bacterial cell wall components
e.g., lipopolysaccharide of gram-negative bacteria
e.g., teichoic acid of gram-positive bacteria
- this is NOT dependent on the acquired immune response
- involves factors: B, I, P
complement activation: what is the membrane attack complex? how is it activated and what is its role?
- activation of C3 convertase is the major amplification step
- this triggers the formation of the membrane attack complex via C5-9
- the membrane attack complex makes holes in membranes
- complement fragments that are released during complement activation play various roles in the immune response
cytokines
- small protein messengers
- immunomodulatory function
- autocrine and paracrine dependent action
- examples: IL2, IL6, IL10, IL12, TNF-alpha, TGF-beta
chemokines
- subset of cytokines
- direct recruitment/homing of leukocytes in an inflammatory response
- CCL19 and CCL21 are ligands for CCR7 and important in directing dendritic cell trafficking to lymph nodes
- other examples: IL8, RANTES, MIP-1 alpha and beta
classification of immunodeficiencies
primary (inherited)
- very rare
- >100 types of primary immunodeficiency
secondary (acquired)
- common
- often subtle
- often involves more than 1 component of the immune system
physiological (expected)
- neonates
- elderly
- pregnancy
examples of secondary immunodeficiency
infection:
- HIV
- measles virus
- mycobacterial infection
biochemical disorders:
- malnutrition
- specific mineral deficiencies (zinc, iron)
- renal impairment
malignancy:
- myeloma
- leukaemia
- lymphoma
drugs:
- corticosteroids
- anti-proliferative immunosuppressants
- cytotoxic agents
clinical features of immunodeficiencies
infections:
- 2 major OR 1 major + recurrent minor infections in 1 year
- unusual organisms
- unusual sites
- unresponsive to treatment
- chronic infections
- early structural damage
features suggestive of primary immunodef:
- family history
- young age at presentation
- failure to thrive
components of the innate immune system
cells
- polymorphonuclear cells (neutrophils, eosinophils, basophils): produced in the bone marrow and migrate rapidly to the site of injury
- monocytes and macrophages: monocytes are produced in the bone marrow, circulate in blood and migrate to tissues where they differentiate to macrophages
- dendritic cells
- NK cells
soluble components
- complement
- acute phase proteins
- cytokines and chemokines
phagocytes
- do NOT tend to vary much between individuals
- express cytokine/chemokine receptors that allow them to home into sites of infection
- cells have pattern recognition receptors (e.g., Toll-like receptors) which recognise generic motifs known as pathogen-associated molecular patterns (PAMPs) such as bacterial sugars, DNA and RNA
- cells have Fc receptors to allow the detection of immune complexes
- they also have phagocytic capacity meaning that they can engulf the pathogens
- cells can secrete cytokines and chemokines to regulate the immune response
overview of response to infection
- the presence of an infection in the tissues will stimulate endothelial activation and the expression of adhesion molecules
- neutrophils will mobilise from the bone marrow and enter the blood stream
- they will adhere to the endothelium at the site of damage and migrate into the tissue
- tissue resident macrophages will phagocytose the pathogens
- macrophages will process the antigens and present them to T cells
- neutrophils eventually die and form pus
conditions that cause a failure to produce neutrophils
failure of stem cells to differentiate along myeloid or lymphoid lineage: RETICULAR DYSGENESIS
- autosomal recessive SCID
- you get no lymphoid or myeloid cells
specific failure of neutrophil maturation:
KOSTMANN SYNDROME
- autosomal recessive severe congenital neutropaenia
CYCLIC NEUTROPAENIA
- autosomal dominant episodic neutropaenia
condition that causes a defect of phagocyte migration
Leukocyte adhesion deficiency
- deficiency of CD18
- during an infection, neutrophils will be mobilised from the bone marrow however they will NOT be able to access the site of infection in the tissues
- high neutrophil count in the blood, NO pus formation
condition that causes a failure of oxidative killing mechanisms
chronic granulomatous disease
- absent respiratory burst (inability to generate oxygen free radicals)
- excessive inflammation
- granuloma formation
- lymphadenopathy and hepatosplenomegaly
cytokine deficiency
- there is a cytokine cycle between macrophages and T cells
- patients vulnerable to organisms that infect macrophages
- most of these patients present with atypical mycobacterial infections (and sometimes salmonella)
how do we investigate chronic granulomatous disease?
2 tests
Nitroblue Tetrazolium (NBT)
- changes from yellow to blue
Dihydrorhodamine (DHR)
- becomes fluorescent
- normally, when neutrophils are activated, a respiratory burst takes place and hydrogen peroxide is produced
- both of these tests are looked at the ability of neutrophils to produce hydrogen peroxide and generate oxidative stress
treatment of phagocyte deficiencies
aggressive management of infection
infection prophylaxis:
- antibiotics (e.g., Septrin)
- anti-fungals (e.g., itraconazole)
definitive therapy
- haematopoietic stem cell transplantation
- specific treatment for chronic granulomatous disease: IFN-gamma therapy
what type of infections do NK cell deficiencies increas the risk of?
VIRAL
- herpes simplex
- VZV
- EBV
- CMV
- HPV
treatment of NK cell deficiencies
- prophylactic antiviral drugs (e.g., aciclovir, ganciclovir)
- cytokines to stimulate NK cytotoxic function
- haematopoietic stem cell transplantation (if severe)
phenotype of Kostmann syndrome
recurrent infections with NO neutrophils on FBC
phenotype of leukocyte adhesion deficiency
recurrent infections with HIGH neutrophil count but no abscess formation
phenotype of chronic granulomatous disease
infection with atypical mycobacterium
normal FBC
phenotype of classical NK cell deficiency
severe chickenpox, disseminated CMV infection
deficiency of complement
- may involve the classica, alternate, C3 or final common pathway
- increases susceptibility to bacterial infections
- particularly increases susceptibility to encapsulated bacterial infections (Neisseria meningitides, Haemophilus influenzae, Streptococcus pneumoniae)
clinical phenotype of complement deficiency
- almost ALL patients with C2 deficiency have SLE
- they usually have severe skin disease
- they also have an increased risk of infections
functional complement tests
CH50 is a test of the classical pathway
- testing the activity of C1, 2 and 4, C3 and C5-9
AP50 is the test of the alternate pathway
- testing the activity of B, D, properidin, C3 and C5-9
summary of investigating complement
- C1q deficiency is an inherited form of complement deficiency that tends to present with SLE in childhood
- in patients with C1q deficiency, they will not be able to activate their classical pathway so CH50 will be low
- with C9 or C7 deficiency, both the CH50 and AP50 will be low because the problem lies in the common pathway
- if someone has acquired SLE, they will have low C4 and possibly low C3
- they may also have some dysfunction of the CH50 pathway because they don’t have much complement left
management of complement deficiencies
vaccination
- boost protection mediated by other arms of the immune system
- they should be vaccinated against polysaccharide encapsulated bacteria
- e.g., meningovax, pneumocax, HIB vaccines
phenotype of C1q deficiency
severe childhood-onset SLE with normal levels of C3 and C4
phenotype of C3 deficiency with presence of a nephritic factor
membranoproliferative nephritis and abnormal fat distribution
phenotype of C7 deficiency
meningococcus meningitis with family history of sibling dying of the same condition aged 6
MBL deficiency phenotype
recurrent infections when neutropaenic following chemotherapy but previously well
summary of types of primary immunodeficiency
phagocytes
- Kostmann syndrome
- leukocyte adhesion deficiency
- chronic granulomatous disease
natural killer cells
- classical NK deficiency
- functional NK deficiency
complement
- classical pathway deficiencies
- alternative pathway deficiencies
- C3 deficiency
- terminal pathway deficiencies
haematopoietic stem cells
- reticular dysgenesis
cytokines
- IL12 and IL12 receptor deficiency
- IFNgamma and IFNgamma receptor deficiency
lymphoid precursors
- severe combined immunodeficiency
T cells
- 22q11.2 deletion syndrome
- bare lymphocyte syndrome
B cells
- X-linked agammaglobulinaemia
- X-linked hyperIgM syndrome
- common variable immunodeficiency
- IgA deficiency
causes of microcytic anaemia
- iron deficiency
- thalassaemia trait
- anaemia of chronic disease
is anisopoikilocytosis (in the context of microcytic anaemia) more associated with iron deficiency or thalassaemia trait?
iron deficiency
causes of aggregated ribosomal material on blood film
- beta-thalassaemia trait
- lead poisoning
- alcoholism
- sideroblastic anaemia
hypersegmented neutrophils - feature of which type of anaemia
megaloblastic
(reflected impaired DNA synthesis)
causes of megaloblastic anaemia
- B12 deficiency
- folate deficiency
- drugs
causes of target cells
- iron deficiency
- thalassaemia
- hyposplenism
- liver disease
what are Howell-Jolly bodies? cause?
nuclear remnants visible within RBCs
- hyposplenism
causes of iron deficiency
- blood loss
- poor diet
- malabsorption
- combinations of the above
causes of megaloblastic change
B12/folate deficiency:
- poor diet
- malabsorption
- pernicious anaemia
causes of hyposplenism
absent spleen
- therapeutic
- trauma
poorly-functioning spleen
- IBD
- coeliac disease
- SCD
- SLE
deficiency seen in coeliac disease
iron, B12, folate, fat, calcium
deficiency seen in crohn’s
B12, bile salts
deficiency seen in pancreatic disease
fat, calcium, B12
deficiency seen in infective/post-infective disease
fat, folate
gold standard investigation for coeliac disease
upper GI endoscopy and distal duodenal biopsies
which HLA mutation is most commonly associated with coeliac
HLA DQ2
coeliac disease: T-cell response to gluten
- peptides from gluten (i.e., gliadin) are deamidated by tissue transglutaminase
- the deamidated gluten is taken up by antigen-presenting cells
- it is then presented by HLA molecules to CD4+ T cells
- CD4+ T cell activation results in secretion of IFN-gamma and may directly lead to increased IL-15 secretion
- the cytokines promote activation of the intra-epithelial lymphocytes
- these T-cells are gamma-delta T cells
- these intra-epithelial lymphocytes kill epithelial cells via the NKG2D receptor
- in other words, the intraepithelial lymphocytes cause damage to the gut wall and lead to the presentation of coeliac disease
coeliac disease: B cell response to gluten
- there may be B cells whose antibodies recognise gliadin
- the B cells will process the antigens and present them via the HLA molecule to the CD4+ T cell
- these primed T cells will then be able to provide help to the B cells that are trying to undergo germinal centre reactions
- the B cells will then undergo isotype switching and affinity maturation to become memory cells and plasma cells which will produce antibodies that are specific for gliadin
serological tests for coeliac disease
IgA anti-transglutaminase antibody
IgA anti-endomysial antibody
NB: both anti-TTG and anti-endomysial antibody assays routinely measure IgA antibodies, and so these are not useful in IgA deficient patients. 1 in 600 are IgA deficient.
coeliac histology: key features
- villous atrophy with crypt hyperplasia
- intra-epithelial lymphocytes
conditions other than coeliac that are associated with increased intraepithelial lymphocytes
- dermatitis herpetiformis
- giardiasis
- cows milk protein sensitivity
- IgA deficiency
- tropical sprue
- post-infective malabsorption
- drugs (NSAIDs)
- lymphoma
complications of coeliac
- malabsorption
- osteomalacia and osteoporosis
- neurological disease (epilepsy, cerebral calcification)
- lymphoma: multi-focal T cell lymphoma, very difficult to treat
consequences of undiagnosed coeliac disease
deficiencies:
- iron deficiency
- folate/B12 deficiency
- vit D and vit K deficiency
- dietary compliance protects against malignancy
- often feel better physically and psychologically
- NB: malabsorption can lead to reduced absorption of medications (e.g., thyroid)
- mortality of untreated: 2-3x general population (lymphoma, infection)
- mortality returns to normal after gluten-free for 3-5 years
components of the adaptive immune system
T lymphocytes
- CD4 T cells
- CD8 T cells
B lymphocytes
- B cell
- plasma cells
- antibodies
soluble components
- cytokines and chemokines
lymphoid development
- lymphocytes are derived from stem cells in the BM
- some will progress along the T cell lineage - they will leave the BM and undergo thymic selection before exiting as mature CD4 and CD8 T cells
- on the other hand, the cells can leave the bone marrow as Pro B cells or Pre B cells which then become IgM B cells
- these can undergo germinal centre reactions and mature into memory B cells and plasma cells
what is reticular dysgenesis?
- most severe form of severe combined immunodeficiency (SCID)
- mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)
Failure of production of:
- lymphocytes
- neutrophils
- monocyte/macrophages
- platelets
fatal in very early life unless corrected with BM transplantation
NB: it is called severe combined because it affects both B and T lymphocytes
X-linked SCID
- most common form of SCID (45%)
Caused by mutation of common gamma chain on chromosome Xq13.1: - this is a component of many cytokine receptors including IL2, IL4, IL7, IL9, IL15, IL21
- the inability to respond to cytokines causes early arrest of T cell and NK cell development and the production of immature B cells
Phenotype:
- very low or absent T cell numbers
- normal or increased B cell numbers (but low immunoglonulin)
- very low or absent NK cell numbers
ADA deficiency
- 16.5% of all SCID
- caused by adenosyne deaminase deficiency
- ezyme required by lymphocytes for cell metabolism
- failure of maturation along any of the lineages
Phenotype:
- very low/absent T cell numbers
- very low/absent B cell numbers
- vely low/absent NK cell numbers
clinical phenotype of SCID
- unwell by 3 months of age; for the first 3 months they are protected by maternal IgG
- infections of all types
- failure to thrive
- persistent diarrhoea
- unusual skin disease
- Fx of early death
T lymphocyte maturation
- arise from haematopoietic stem cells
- exported as immature cells to the thymus where they undergo selection
- CD8+ T cells recognise peptides presented by HLA class I molecules
- CD4+ T cells recognise peptides presented by HLA class II molecules
- mature T lymphocytes enter the circulation and reside in secondary lymphoid organs
selection and central tolerance - T cells
- if the T cell has very low affinity for HLA then it is useless and so will not be selected
- if they have very high affinity then they are dangerous because they can give rise to autoreactivity - so these are also negatively selected and die
- so, you are left with the T cells that have intermediate affinity for HLA (about 10%)
- they will then differentiate further depending on which type of HLA molecule they show intermediate affinity to
- intermediate affinity for HLA class I; differentiate as CD8+ T cell
- intermediate affinity for HLA class II; differentiate as CD4+ T cell
CD8+ cytotoxic T cells
- specialised cytotoxic cells
- recognise peptides derived from intracellular proteins in association with HLA class I (HLA-A, HLA-B, HLA-C)
- kills cell directly
a) perforin and granzymes
b) expression of Fas ligand (which binds to Fas and induces apoptosis) - secrete cytokines
- particularly important in defence against viral infections and tumours
CD4+ Helper T cells
recognise:
- peptides derived from extracellular proteins
- presented on HLA class II molecules (HLA-DR, HLA-DP, HLA-DQ)
immunoregulatory functions via cell:cell interactions and expression of cytokines
- provide help for development of a full B cell response
- provide help for development of some CD8+ T cell responses
22q11.2 Deletion syndromes (e.g., Di George syndrome)
the thymus does NOT fully develop.
developmental defect of the pharyngeal pouch.
Facial abnormalities:
- high forehead
- low set, abnormally folded ears
- cleft palate
- small mouth and jaw
other features:
- underdeveloped parathyroid gland (resulting in hypocalcaemia)
- oesophageal atresia
- underdeveloped thymus
- complex congenital heart disease
consequences of underdeveloped thymus:
- normal B cells
- low T cell numbers
- homeostatic proliferation with age: if T cells are in an empty compartment they will just keep proliferating, so, in the end, T cell numbers tend to increase with age
- immune function is mildly impaired and tends to improve with age
clinical features of T lymphocyte deficiencies
- viral infections (e.g., CMV)
- fungal infections (e.g., PCP, cyptosporidum)
- some bacterial infections, esp. intracellular organisms (TB, salmonella)
- early malignancy
investigation of T cell deficiencies
- total white cell count and differential (NB: lymphocyte count is much higher in children)
- lymphocyte subsets (quantify CD4, CD8, B cell, NK cell)
- immunoglobulins (if CD4 T cell deficient, they will have IgM but no IgG or IgA)
- functional tests of T cell activation and proliferation
- HIV test
management of immunodeficiency involving T cells
- aggressive prophylaxis/treatment of infection
- haematopoietic stem cell transplantation (to replace abnormal populations in SCID, to replace abnormal cells)
- enzyme replacement therapy (PEG-ADA for ADA-SCID)
- gene therapy (stem cells are treated ex vivo with viral vectors containing missing components. transducent cells have a survival advantage in vivo)
- thymic transplantation (to promote T cell development in Di George syndrome)
central tolerance - B cells
no recognition of self in bone marrow - survive
recognition of self in bone marrow - negative selection to avoid autoreactivity
B cell antigen encounter
- when B cells encounter antigens, the early response tends to be an IgM response (not T cell dependent)
- they will differentiate to form IgM memory cells and plasma cells
- they also undergo a T cell dependent germinal centre reaction
- dendritic cells will prime the CD4+ T cells
- then, these CD4+ T cells help with B cell differentiation (this interaction requires CD40 ligand expression on T cells, and CD40 expression on B cells)
- once they have received this help from CD4+ T cells, the B cells can proliferate and undergo somatic hypermutation (to refine their receptor to develop high affinity) and they can isotype switch (to IgA, IgG and IgE)
- this results in the production of much higher affinity memory cells and plasma cells
immunoglobulins
- soluble proteins made up of 2 heavy chains and 2 light chains
- the heavy chain determines the antibody class
- there are also subclasses of IgG and IgA
- antigen is recognised by the antigen binding region (Fab) of both the heavy and light chains
- effector function is determined by the constant region of the heavy chain (Fc)
Antibody function:
1) identification of pathogens and toxins (Fab-mediated)
- particularly important against extracellular pathogens
2) interacts with other components of the immune response to remove pathogens (Fc-mediated)
- complement
- phagocytes
- NK cells
3) important in defence against bacteria of all kinds
Bruton’s X-linked Hypogammaglobulinaemia
- this affects B cells at the point at which they emerge from the bone marrow
- in this condition, you do NOT have B cells maturing and, as such, you do NOT have any antibodies being produced
- caused by an abnormal B cell tyrosine kinase (BTK) gene
- this means that pre-B cells cannot develop into mature B cells
- therefore, there is an absence of mature B cells
- once maternal IgG is out of the system (around 3 months), they will have NO ANTIBODIES
clinical phenotype of Bruton’s X-linked Hypogammaglobulinaemia:
- boys present in the first few years of life
- recurrent bacterial infections
- viral, fungal, parasitic infections
- failure to thrive
