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Pathology > Immunology > Flashcards

Immunology Flashcards

1
Q

Principles of the immune system

A

detect, respond and eliminate pathogens
maintain tolerance to self, environmental antigens and in pregnancy paternal antigens
induce memory (more rapid and greater response) to previously encountered infection/vaccines
restore organ/tissue homeostasis (resolution of inflammation, repair injury) after elimination of pathogen

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2
Q

overview of immune response to infection

A

cell death or extensive damage –> molecular PAMP or host DAMP –> type 1 and 3 immune responses

cell stress or tissue perturbation –> host DAMP (more than microbial PAMP) –> type 2 immune response

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3
Q

Innate immunity

A

pathogens: viruses, bacteria, fungi, parasites, ticks

sensors: epithelial cells, tissue macrophages, dendritic cells, mast cells, sensory neurons, complement

actions: enhance barrier function, secrete cytokines, chemokines and interferons, activate complement, recruit circulating neutrophils and monocytes, induce adaptive immune responses in secondary LT, internal (phagosome) and external pathogen (cell degradation) killing

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4
Q

type 1 immune response to intracellular pathogens

A

CD4 T cells activated and induce activation of CD8 T cells and macrophages (via IFN-gamma)

B cells give rise to IgG and IgA responses via germinal cells (IgG>IgA)

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5
Q

type 3 immune responses to extracellular bacteria and fungi

A

CD4 Th1 cell secretes IL-17 to activate neutrophils and IL-22 to promote epithelial cell integrity and secretion of antimicrobial proteins by epithelial cells

B cells induce IgA and IgG immune response via germinal cells (IgA>IgG)

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6
Q

type 2 immune response to extracellular parasites

A

CD4 Th2 cells secreta IL-4 IL-5 IL-13 to activate mast cells, basophils and eosinophils

B cells –> germinal cells –> IgE

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7
Q

innate-like B cell

A

spontaneous IgM production

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8
Q

long-lived plasma cells vs memory

A

memory = secondary back-up with lower affinity (can recognise other strains of same organism)

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9
Q

Immunoglobulins

A

structure: 2 heavy and light chains
Fab: antigen recognition, positive selection/glycosylation in LN GC, neutralisation of toxins/virulence factor
Fc subunit: effector function, isotype class switching, Ig subclasses, modification of hinge region, glycosylation, affinity to Fc receptors

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10
Q

Biological activity of IgG FcR binding

A

antibody Fc region provides mechanistic link between antigen specific V-domain and 4 main effector functions:
- activation of complement
- clearance and elimination of antibody coated pathogens (opsonisation, phagocytic, ADCC, mast cell degeneration)
- transport and delivery of Ig to different body compartments
- regulation of immune responses (B cell activation, antibody affinity maturation, IgG production, DC function)

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11
Q

Inborn errors of immunity (IEI)

A

heterogeneous group of genetic disorders resulting in immune dysfunction and ill health
almost 500 single gene defects identified impacting the immune response

most common: pure antibody deficiency syndromes

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12
Q

Inborn errors of immunity with multiple episodes of a wide range of infection

A

common organisms and rare opportunistic infections and live vaccines
Children > adults
high or complete penetrance
SCID, XLA, CGD

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13
Q

Inborn errors of immunity with susceptibility to weakly virulent organisms only

A

environmental TB species and BCG vaccine
familial disease

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14
Q

Go back and make flashcards for other two ‘Inborn errors of immunity with’

A
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15
Q

genetic susceptibility to TB

A

monogenic genetic IL-12 receptor associated with TB in children (very rare)
P1104A variant of TYK2 associated with increased risk (found in 4% of european ancestry
variant impairs IL-23 but not IL-12

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16
Q

Susceptibility to infection and autoimmune/auto-inflammatory disease

A

= gain of function in immune-related gene

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17
Q

autoimmune diseases due to inborn errors of immunity

A

characteristic feature is presence of pathological self-reactive T cell immune responses
result from inborn errors of: T cell tolerance, apoptosis, regulatory function
hypomorphic (partial loss of function) SCID gene defects
early presentation of autoimmune diseases that are very hard to treat

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18
Q

autoinflammatory disease due to IEI

A

aberrant activation of innate inflammatory pathways in the absence of antigen directed autoimmunity

clinical presentation: fever, skin rashes, arthritis

2 major categories: IL-1 inflammasomopathies (familial mediterranean fever), type 1 interferonopathies (aicardi goutiers syndrome)

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19
Q

Allergic disorders due to IEI

A

eczema, eosinophilia and elevated IgE can be a manifestation of IEI
present with severe atopic diseases, refractory to standard therapy, high level of TH2 biomarkers AND increased susceptibility to infection, autoimmune diseases, skeletal and vascular abnormalities and neuro-developmental delay
autosomal dominant STAT-3 loss of function is prototype for hyper IgE syndrome

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20
Q

early onset viral related cancers and IEI

A

EBV can cause Hodkins and non-Hodgkins lymphoma
combined immune deficiency syndromes affecting CD8 T cells NK cells - impairment due to deficiency of perforin or molecule involved in release of cytolytic granules, loss/ reduction of proximal signalling molecules in T cell and NK activation

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21
Q

clinical presentation of IEI

A

heterogeneous
minor symptoms: selective IgA deficiency
modest symptoms: common variable immune deficiency supported by weekly or monthly IgG therapy
life-threatening: SCID unless corrected by BMT and/or gene therapy

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22
Q

Presentation of IEI (infection)

A

Severe (sepsis)
Persistent
Unusual infections (opportunistic)
Recurrent ( > 2 episode pneumonia in a year, > 8 episodes of otitis media in child)

consider possibility of IEI in conditions arising from complication of recurrent infections (eg. bronchiectasis and chronic rhino-sinusitis)

early onset or refractory autoimmune cytopenias
very early onset inflammatory disease, Haemophagocytic
Lympohistiocytosis (HLH), unexplained inflammatory skin disease,
granulomatous disease,
Difficult to treat allergic skin disease with systemic features to suggest
possibility of IEL ( infection, autoimmune disease etc)
Unexplained viral induced cancers in patient less than 40 year
EBV lymphoproliferative disease
HPV cutaneous warts
Family history of immune deficiency and/or consanguinity

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23
Q

First-line blood tests for immunodeficiency (FISH)

A

FBC
Immunoglobulins
Serum complement
HIV test (18-80 years)

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24
Q

Tests to exclude secondary immune deficiency

A

renal and liver profile
calcium and bone profile
total protein and albumin
urine protein/Cr ratio
serum protein electrophoresis
serum free light chains

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25
Q

second-line tests for immune deficiency

A

concentration of vaccine antibodies
analysis of lymphocyte subsets using flow cytometry

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26
Q

third line tests to diagnose immune deficiency

A

genetic tests

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27
Q

Serum Igs roles

A

IgG is key to host defence in alveoli (equilibrium with blood)
secretory IgA and IgM protect upper and lower airways - originate from mucosal B cells rather than blood

risk of pneumonia increases with IgG level < 4.0g/L

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28
Q

Extra-follicular B cells

A

recognise protein
t cell dependent and independent
rapid response (24-96 hours)
class switching
memory
short lived plasma cells

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29
Q

Marginal zone b cell

A

recognise encapsulated organisms (carbs)
t cell independent
IgM > IgA and IgG
limited memory and antibody affinity
made in spleen/GI tissue
pre-diversity Ig repertoire

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30
Q

Germinal centre B cells

A

recognise protein
T cell dependent
5-7 days response
class switching
memory
affinity maturation
long lived plasma cells

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31
Q

Neutrophils

A

largest innate cell population in blood: continuous production by bone marrow regulated by IL-17 G-CSF axis
found in bone marrow, LN, lung, spleen
first line: recruited from blood
eliminate pathogens : phagocytosis, degranulation, NETosis
healing and repair tissue damage
modulate adaptive immune responses: promote T cell independent antibody production, enhance or suppress T cell function

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32
Q

inborn errors affecting neutrophils

A

defective binding to endothelial cells: leukocyte adhesion deficiency syndrome
defective generation of reactive oxygen species (chronic granulomatous disease)

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33
Q

Chronic benign neutropenia

A

Mild (usually) or moderate neutropenia
Common in number of ancestry groups (Africa, Middle East)
Associated with SNP in DARC gene which leads to absent expression
Asymptomatic ( should not lead to further investigation)

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33
Q

Familial idiopathic neutropenia

A

Adult onset
Moderate, severe neutropenia
Associated with organ specific autoimmune disease
Usually no significant increase risk of infection

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34
Q

Severe congenital neutropenia

A

Defects in neutrophil maturation: present < 3 months
Genetic syndromes (neutrophil elastase)
Genetic defects which may also involve other organ systems (Kostmann, SDS)
Pre-malignant conditions (MDS and AML)
Susceptible to oral, cutaneous and epithelial Staph aureus, G- enteric bacteria and fungal infection
G-CSF support and stem cell transplantation for high risk individuals

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35
Q

Failure of neutrophil migration

A

Leukocyte adhesion deficiency
Deficiency of CD18 (β2 integrin subunit)

CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration

Lack of expression of adhesion molecules results in failure to exit from the bloodstream
delayed separation of umbilical cord
very high neutrophil counts in blood (20-100 x106/L)
Absence of pus formation

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36
Q

Chronic granulomatous disease

A

Absent respiratory burst
Deficiency of one of components of NADPH oxidase
Inability to generate oxygen free radicals results in impaired killing, NETosis.

Skin, lymph node, liver, bone, chest bacterial , fungal, TB and NTM infections

Excessive inflammation
NADPH: leads to increased NF-κ β and IL-1β activation
Macrophage infiltration and granuloma
Gastro-intestinal and genitourinary inflammatory disease
Management
Cotrimoxazole and itraconazole prophylaxis
Adjunctive IFN-, Stem cell and gene therapy

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37
Q

Investigation of neutrophil IEI syndromes

A

Immunoglobulins
Lymphocyte subsets
Bone marrow biopsy
Neutrophil function assay
Neutrophil oxidative burst
Stimulate neutrophils and measure hydrogen peroxide
DHR-123 assay: DHR-13 is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide
Genetic neutrophil panels

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38
Q

Complement

A

Complement protein network:
Complement cascade proteins (C3, C4)
Complement regulatory protein (C1 inhibitor, Factors B,D, P, H I, CD46, CD55, CD59)
Complement receptors (CR1-4)

Complement function:
Induction of acute inflammatory responses (C3a, C5a)
Opsonisation of pathogens (C3b)
Removal of immune complexes (C1q-CR1)
Control of Neisseria infection (C5-9)
Regulation of B and T cell immune responses (C3d)

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39
Q

Complement protein deficiencies

A

Classical complement C1-C4-2
SLE ( C1q: 90% will develop SLE)
Susceptibility to encapsulated bacterial infections
Haemophilus influenzae type b
Streptococcus pneumoniae

Alternative Pathway
Neisseria meningitis (Properdin)

C3
Pyogenic bacterial infection
C3 glomerulopathy

Terminal complement pathway deficiency
Neisseria meningitis infection
Disseminated gonococcal infection

MBL deficiency
5-30% of population: not clinically significant

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40
Q

Deficiency of complement regulatory proteins

A

C1 inhibitor deficiency
Recurrent episodes of angioedema (skin, abdomen, larynx)
Bradykinin mediated angioedema
Low C4 normal C3 absent C1 inhibitor function
Emergency therapy with C1 inhibitor (NOT Adrenaline)
Maintenance therapy (C1 inhibitor concentrate, icatibant (bradykinin antagonist) kallikrein antagonist (ecallitanide and lanadelumab)

Factor H, I, MCP (CD46) regulate C3 levels
C3 glomerulopathy
Atypical Haemolytic uraemic syndrome
Low C3 normal C4 absent alternative pathway function (AP50)

CD55 and CD59
Adult presentation
Triad haemolysis, thrombosis and pancytopaenia

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41
Q

Investigation of complement function

A

FBC
Serum immunoglobulin
Lymphocyte subsets
C3 and C4
Functional complement tests: CH50 classical pathway, AP50 alternative pathway
Complement genetic test

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42
Q

Complement deficiencies management

A

Vaccination:
Boost protection mediated by other arms of the immune system
Tetravalent Meningococcal vaccine , Pneumovax and HIB vaccines

Prophylactic antibiotics

Treat infection aggressively

Screening of family members

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43
Q

Primary lymphoid organs

A

= Organs involved in lymphocyte development

Bone marrow:
Both T and B lymphocytes are derived from haematopoetic stem cells
Site of B cell maturation

Thymus:
Site of T cell maturation.
Most active in the foetal and neonatal period, involutes after puberty

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44
Q

Severe combined immunodeficiency (SCID)

A

results from defects in generation of lymphoid precursors in bone marrow
absence or dysfunction of T cells affecting both cellular and humoral immunity

Mechanistic basis for SCID: more 20 possible pathways:
Metabolic diseases which inhibit lymphocyte development
Absent or impaired cytokine signal transduction pathways
Defects in V (D)J recombination resulting in failure to generate antigen specific T and B cell receptor
Failure to form functional T cell receptor complex (mutations in TCR signal transduction proteins)
Abnormalities in stromal component of thymus

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45
Q

SCID clinical features

A

Children: onset of disease less than 1 year, fatal if immune defect is not corrected with 2 years
Multiple, recurrent opportunistic infections involving many organs
Autosomal recessive or X-linked inheritance
Complete penetrance
Inherited from the parental genome
Unwell by 3 months of age
Persistent viral, chest and GI infection (para-influenza -3, adenovirus )
Opportunistic infections (Pneumocystis jirovecii, CMV, )
Live vaccine infection (BCG, rotavirus)
Persistent or severe mucosal and/or skin candida infection
Failure to thrive
Unusual skin disease
Graft versus host disease
Bacterial infection rare
Family history of early infant death

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46
Q

Diagnosis of SCID

A

Low lymphocyte count (counts are normally much higher in children than in adults

CD3 T cell count < 300cells/uL

T cell proliferation < 10% of control

Low serum immunoglobulins

Flow cytometry
T- B+ SCID
T-B-SCID

Targeted gene panels

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47
Q

SCID treatment

A

Stem cell transplantation
HLA matched sibling
HLA matched unrelated donor
Haplo-identical donor

Outcomes best
Age less than 3.5 months
No infection
Matched sibling donor
Survival from all donors equivalent of no infection present

Early diagnosis improve outcomes

No suitable donors: gene therapy

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48
Q

SCID gene therapy

A

remove, isolate and grow CD34 then expose to retroviral vector and reinsert

Initial trials for X-Linked SCID led to restoration of T cell immunity but complicated by T cell leukaemia in 20% of recipients

Development of safer viral vectors has reduced risk of T cell leukaemia

Application of reduced conditioning to allow space in bone marrow for engraftment of gene transfected Stem cell has allowed much better restoration of B cell function

Approved for ADA-SCID in Europe

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49
Q

Screening for SCID: TREC analysis

A

Generation of a T cell receptor is associated with formation of DNA extra-chromosomal ‘by-product’ called the T-cell receptor excision (TREC)

Measurement of TREC in blood is a good biomarker of thymic function and can be used to identify low T cell counts in neonates

Flow cytometry is then used to enumerate T cell counts in patients with low TREC counts and direct further investigation

Results of TREC screen in the USA show
SCID is more common than expected
Improved outcomes following SCT

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50
Q

22q11.2 deletion syndrome

A

Most common chromosomal deletion syndrome

Occurs 1 in 1000 foetuses, 90% de novo deletions

Developmental failure of pharyngeal arch (craniofacial structures, thymus, parathyroid glands aortic arch and cardiac outflow tract

Original description was clinical triad of immune deficiency hypoparathyroidism and congenital heart disease

Now known to have heterogeneous presentation multiple additional congenital abnormalities (face, kidney), ENT, gastrointestinal, cognitive, behavioural and psychiatric features

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51
Q

22q11.2 deletion syndrome and immune deficiency

A

5% of children have reduced T cells number which usually resolve in early childhood

Much smaller proportion of children present with SCID phenotype and thymic transplantation has emerged as a useful option

Increased incidence of autoimmune disease (ITP) and humoral defects with age

Sino-pulmonary infection more often secondary to underlying structural upper airway disease with added subtle antibody defect (patient may benefit from antibiotic prophylaxis over winter)

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52
Q

secondary lymphoid tissues

A

site of T and B cell activation by APC
distinct functional subunits:
B cell area = germinal centres (positive selection for antigen specific B cells)

lymph nodes
spleen (unique function: removes aged red cells)
Mucosal lymphoid tissues - tonsils, adenoids, peyer’s patches, isolated lymphoid follicles

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53
Q

Selective IgA deficiecnt

A

Commonest primary antibody deficiency syndrome: incidence influenced by geography: 1 in 163 in Spain to 1: 14,840 in Japan

Diagnosis: serum IgA less than 0.07g/L with normal serum immunoglobulins, vaccine responses and B and T cell counts

30% of individual are symptomatic
Allergic disorders
Sino-pulmonary and enteric infections
Autoimmune disease (CD, ITP, SLE, AITD, and Type 1 DM)
GI cancers

Must be distinguished from IgA deficiency associated with IgG2 subclass and/or specific polysaccharide antibody deficiency

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54
Q

Common variable immune deficiency (CVID)

A

Antibody deficiency syndrome characterised by
Increased susceptibility to infection
Autoimmune disease
Granulomatous disease
Lymphoproliferative disease

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55
Q

CVID pathogenesis

A

Heterogeneous group of conditions
Defect in B cell function, characterised by failure to make protective antibodies to polysaccharide encapsulated pathogens
Immune defect
Intrinsic B cell defect in development, maturation or function
Insufficient help from CD4 T cells
Aetiology is largely unknown, polygenic disorder however in in a small proportion of patients (5-10%%) monogenic genetic mutation identified

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56
Q

CVID: infection phenotype

A

Recurrent bacterial sino-pulmonary infection with encapsulated bacteria such as Streptococcus pneumoniae and haemophilus influenzae type B

Repeated chest and sinus may result in bronchiectasis, chronic sinusitis in 20-60% of patients

Otiitis media and Haemophilus type b conjunctivitis

Enteric infection with Campylobacter jejeuni and Giardia lamblia, small bowel bacteria overgrowth syndrome

Skin: cellulitis, abscess, HSV and VZV infection

Persistent, severe, recurrent respiratory viral (rhinovirus) and norovirus infections

Normal life expectancy with IgG replacement therapy

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57
Q

CVID complex phenotype

A

20-30% of patients with CVID will experience an autoimmune/inflammatory disorder

Autoimmune disorder in CVID patients (ITP, AIHA, thyroid disease)

Autoinflammatory condition (CVID enteropathy, nodular regenerative hyperplasia and granulomatous hepatitis which can lead to portal hypertension and cirrhosis)

Granulomatous interstitial lung disease: often with granulomatous infiltration in lymph nodes, spleen, skin, liver,

Increased risks of B cell NHL and gastric cancer

Monogenic CVID tend to more common associated with complex CVID phenotypes

Reduced life expectancy: roughly 20% reduction over 20 years

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58
Q

CVID diagnosis

A

Age more than 4 years
Reduction in serum IgG and IgA and/or IgM more than 2 SD below reference interval for healthy controls
Poor vaccine responses to either carbohydrate (pneumovax) and/or protein antigen (tetanus)
Exclusion of other causes of antibody deficiency (B Cell LPD and drugs induced syndromes)

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59
Q

CVID management

A

Standard management for complication of lung disease
Physiotherapy
Sputum surveillance
Saline nebuliser and carbocysteine
Standard antibiotic and airflow obstruction protocols
Address co-morbidities (Sinus disease, GORD, OSA, Asthma )

IgG replacement therapy

Treatment of autoimmune and granulomatous complications of CVID

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60
Q

IgG replacement therapy

A

Only replaces IgG: not IgA and IgM

Intravenous and subcutaneous preparations derived from plasma pools between 1,000 and 10,000 donors (European and from 2021 UK donors)

IgG preparation will contain antibodies to pneumococcus, haemophilus tetanus, measles mumps and Hep A and Hep B

Several different IgG products available
All have similar efficacy
Patient tolerability to different products vary
ADR include fever, headache, myalgia, rash, rigors, anaphylaxis - have to infuse slowly
Supplies of different IgG products can be erratic

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61
Q

X-linked agammaglobulinaemia (XLA)

A

Presentation usually aged less than 5 years
Mutation in BTK gene encoding Bruton Tyrosine Kinase
Recurrent bacterial pyogenic infection involving ear, nose, throat, respiratory and gastrointestinal tract infection
Microbiology: S. pneumoniae, H influenzae S aureus, and Pseudomonas spp:
Virology: unique susceptibility to disseminated enteroviral infection if not on IgG replacement therapy

Autoimmune and inflammatory disease not uncommon

Usually absent all immunoglobulins isotype and marked reduction or absent B cells:
Neutropenia can be a feature of XLA

Family history of male relative on maternal side

Standard management for bronchiectasis and chronic sinusitis with IgG replacement therapy

Chronic or acute lung disease is the most common cause of death

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62
Q

Auto-inflammatory diseases

A

Activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage

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63
Q

Auto-immune diseases

A

Activation of aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens

Organ-specific antibodies may predate clinical
disease by years

Adaptive immune response plays the
predominant role in clinical expression of disease

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64
Q

Monogenic (systemic) auto-inflammatory disease

A

Mutations in a gene encoding a protein involved in a pathway associated with innate immune cell function

Abnormal signalling via key cytokine pathways involving TNF-alpha and/or IL-1 is common

Classically present with
- periodic fevers
- inflammation – eg skin/joint/serosal/CNS
- high CRP

eg. familial Mediterranean fever

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65
Q

Familial Mediterranean fever (FMF)

A

Autosomal recessive condition
Mutation in MEFV gene
MEFV gene encodes pyrin-marenostrin
Pyrin-marenostrin expressed mainly in neutrophils
Failure to regulate cryopyrin driven activation of neutrophils

Clinical presentation:
Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash

Complication - AA amyloidosis
Liver produces serum amyloid A as acute phase protein
Serum amyloid A deposits in kidneys, liver, spleen

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66
Q

FMF diagnosis & treatment

A

Investigation:
High CRP, high SAA
Blood sample to specialist genetics laboratory to identify MEFV mutation

Treatment:
Colchicine 500mcg bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion
IL-1 blocker (anakinra, canukinumab)
TNF alpha blocker

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67
Q

Monogenic auto-immune diseases

A

Mutation in a gene encoding a protein involved in a pathway associated with adaptive immune cell function

Abnormality of regulatory T cells - IPEX

Abnormality of lymphocyte apoptosis - ALPS

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68
Q

IPEX

A

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked

Mutations in Foxp3 (Forkhead box p3) which is required for development of CD25+Treg cells

Failure to negatively regulate T cell responses
Autoreactive B cells
limited repertoire of autoreactive B cells

Presentation:
Diabetes Mellitus
Hypothyroidism
Enteropathy
Eczema

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69
Q

ALPS

A

Autoimmune lymphoproliferative syndrome

Mutations within FAS pathway
Eg mutations in TNFRSF6 which encodes FAS
Disease is heterogeneous depending on the mutation

Defect in apoptosis of lymphocytes
Failure of tolerance
Failure of lymphocyte ‘homeostasis’

Presentation:
High lymphocyte numbers with large spleen and lymph nodes
Auto-immune disease
commonly auto-immune cytopenias
Lymphoma

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70
Q

Polygenic auto-inflammatory diseases

A

Mutations in genes encoding proteins involved in pathways associated with innate immune cell function

Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage

HLA associations are usually less strong

In general these disease are not characterised by presence of auto-antibodies

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71
Q

Inflammatory bowel disease

A

Familial association studies and twin studies suggested genetic predisposition to disease
15% patients have an affected family member
50% vs <10% disease concordance in monozygotic vs dizygotic twins

> 200 disease susceptibility loci found

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72
Q

Crohn’s disease

A

IBD1 gene on chromosome 16 identified as NOD2 (CARD-15, caspase activating recruitment domain -15).

Three different mutations of this gene have each been shown to be associated with Crohn’s disease.

NOD2 gene mutations are present in 30% patients (ie not necessary)

Abnormal allele of NOD2 increases risk of Crohn’s disease by 1.5-3x if one copy and 14-44x if two copies (ie not sufficient)

NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells
Intracellular receptor for muramyl dipeptide on bacterial products and promotes their clearance

Mutations also found in patients with Blau syndrome and some forms of sarcoidosis

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73
Q

Crohn’s presentation & treatment

A

Clinical features:
Abdominal pain and tenderness
Diarrhoea (blood, pus, mucous)
Fevers, malaise

Treatment may include:
Corticosteroid
Anti-TNF alpha antibody

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74
Q

Mixed pattern immunological diseases

A

Mutations in genes encoding proteins involved in pathways associated with innate immune cell function

And

Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function

HLA associations may be present

Auto-antibodies are not usually a feature

Examples:
Axial spondyloarthritis
Psoriatic arthritis
Behcet’s syndrome

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75
Q

Axial spondyloarthritis

A

Highly heritable - 90% of the risk of developing disease is genetic

HLA-B27 accounts for 50% overall genetic risk

Enhanced inflammation occurs at specific sites where there are high tensile forces
(entheses - sites of insertions of ligaments or tendons)

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76
Q

AS presentation & treatment

A

Presentation
Low back pain and stiffness
Enthesitis
Large joint arthritis

Treatment
Non-steroidal anti-inflammatory drugs
Immunosuppression
Anti-TNF alpha
Anti-IL17

(diagnosis: clinical & MRI)

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77
Q

Polygenic auto-immune diseases

A

Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function (including HLA molecules)

Aberrant T and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens

Auto-antibodies are found – reflecting development of B cell response

Examples:
Rheumatoid arthritis
Systemic lupus erythematosus
Myaesthenia Gravis
Primary biliary cholangitis
Pernicious anaemia
Addison disease

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78
Q

Genetic polymorphisms - HLA associations

A

HLA presentation of antigen is required for development of T cell and T cell-dependent B cell responses

HLA-DR15: 10 fold risk of goodpasture disease
HLA-DR3: 4 fold risk of Graves and 6 fold risk of SLE
HLA-DR3/DR4: 25 fold risk of T1DM
HLA-DR4: 4 fold risk of RA

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79
Q

PTPN22 (genetic polymorphisms)

A

Protein tyrosine phosphatase non-receptor 22
Lymphocyte specific tyrosine phosphatase which suppresses T cell activation
Allelic variants found in SLE, RA, T1DM

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80
Q

CTLA4 (genetic polymorphisms)

A

Cytotoxic T lymphocyte associated protein 4
Expressed by T cells and transmits inhibitory signal to control T cell activation
Allelic variants found in SLE, RA, T1DM, auto-immune thyroid disease

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81
Q

Gel and Coombs classification of polygenic autoimmune diseases

A

Type I: Anaphylactic hypersensitivity
- Immediate hypersensitivity which is IgE mediated – rarely self antigen

Type II: Cytotoxic hypersensitivity
- Antibody reacts with cellular antigen

Type III: Immune complex hypersensitivity
- Antibody reacts with soluble antigen to form an immune complex

Type IV: Delayed type hypersensitivity
- T-cell mediated response

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82
Q

Type II antibody driven auto-immune disease

A

Goodpasture:
auto-antibody binds to non-collagenous domain of basement membrane collagen type IV leading to glomerulonephritis and pulmonary haemorrhage

Pemphigus vulgaris:
auto-antibody binds to epidermal cadherin leading to skin blistering

Graves:
auto-antibody binds to TSH receptor and causes sustained activation -> hyperthyroidism

Myasthenia Gravis:
auto-antibody binds to ACh receptor and causes blockade –> muscle weakness

83
Q

Immunopathogenic mechanisms in type III responses

A

Immune complex formation and deposition in vessels –> complement activation & infiltration of macrophages and neutrophils –>
Cytokine and chemokine expression
Granule release from neutrophils
Increased vascular permeability –>

Inflammation and damage to vessels
Cutaneous vasculitis
Glomerulonephritis
Arthritis

84
Q

Type III driven autoimmune diseases

A

SLE:
auto-antibodies against histones, DNA and RNP –> rash, glomerulonephritis, arthritis

85
Q

Type IV T cell-mediated disease

A

Insulin-dependent (type 1) diabetes mellitus:
auto-antibodies against pancreatic beta cells –> beta cell destruction by CD8+ T cells

86
Q

Graves disease

A

Excessive production of thyroid hormones

Mediated by IgG antibodies which stimulate the TSH receptor
Evidence
Antibodies stimulate thyrocytes in vitro
Passive transfer of IgG from patients to rats often produces similar symptoms (!)
Babies born to mothers with Graves may show transient hyperthyroidism

Stimulating autoantibodies against TSH-receptor bind to receptor
Act as TSH agonists
Induce uncontrolled overproduction of thyroid hormones
Negative feedback cannot override antibody stimulation

87
Q

Hashimoto thyroiditis

A

Commonest cause of hypothyroidism in iodine-replete areas
Goitre – enlarged thyroid infiltrated by T and B cells
Associated with anti-thyroid peroxidase antibodies
Presence correlates with thyroid damage and lymphocyte inflammation
Some shown to induce damage to thyrocytes
Associated with presence of anti-thyroglobulin and anti-thyroid peroxidase antibodies

diagnosis: clinical & thyroid biochemistry

88
Q

Type 1 diabetes mellitus

A

Antibodies pre-date development of disease

Anti-islet cell antibodies
Anti-insulin antibodies
Anti-GAD antibodies
Anti-IA-2 antibodies

Individuals with 3-4 of the above are highly likely
to develop type I diabetes

Detection of antibodies does not currently play a role in diagnosis

89
Q

Pernicious anaemia

A

Failure of vitamin B12 absorption
Vitamin B12 deficiency
Macrocytic anaemia
Neurological features with subacute combined degeneration of cord (posterior and lateral columns), peripheral neuropathy, optic neuropathy

Antibodies to gastric parietal cells or intrinsic factor - are useful in diagnosis

90
Q

Coeliac disease auto-antibodies

A

anti-TTG and anti-endomyosial antibodies

91
Q

IBD auto-antibodies

A

P-ANCA (UC>Crohn’s)

92
Q

Liver disease autoantibodies

A

Autoimmune hepatitis:
ANA, SMA, anti-LKM, P-ANCA

PBC:
ANA, AMA, P-ANCA

93
Q

Myasthenia gravis

A

Anti-acetylcholine receptor antibodies present in
~75% patients and are useful in diagnosis

Offspring of affected mothers may experience
transient neonatal myaesthenia

also have anti-striational antibodies

94
Q

RA genetic predisposition

A

HLA DR4 (DRB1 0401, 0404, 0405) and HLA DR1 (DRB1 0101) alleles

(Susceptible alleles share a sequence at positions 70-74 of the HLA DR beta chain. These alleles may bind ‘arthritogenic peptides’ and have been shown to bind to citrullinated peptides with high affinity)

Peptidyl arginine deiminase (PAD)2 and PAD4 polymorphisms

(Enzymes involved in deimination of arginine to create citrulline –> polymorphisms increase citrullination)

PTPN22 polymorphism

best test: anti-CCP

RF:
A rheumatoid factor is an antibody directed against the common (Fc) region of human IgG

IgM anti-IgG antibody is most commonly tested although IgA and IgG rheumatoid factors may also be present in some individuals

95
Q

Anti-nuclear antibodies

A

Group of antibodies that bind to nuclear proteins
Test by staining of Hep-2 cells (human epidermoid cancer line)
Very common
Low titre antibodies (<1:80) often found in normal individuals (esp older women)

96
Q

Systemic Lupus erythematosus (SLE)

A

Antibodies bind to antigen (dsDNA) to form immune complexes
Immune complexes deposit in tissues (small vessels)
Skin, joints, kidney
Immune complexes activate complement (classical pathway)
Immune complexes stimulate cells expressing Fc and complement receptors

97
Q

SLE genetic predisposition

A

Abnormalities in clearance of apoptotic cells
Polymyorphisms in genes encoding complement, MBL, CRP

Abnormalities in cellular activation
Polymorphisms in genes encoding/controlling expression of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules

Both of above lead to:

Antibodies directed particularly at intracellular proteins
? Debris from apoptotic cells that have not been cleared
Nuclear antigens - DNA, histones, snRNP
Cytoplasmic antigens - ribosome, scRNP

98
Q

Anti-dsDNA antibodies

A

Measures antibodies against double stranded DNA
Are highly specific for SLE (95%) (false positive rare)
Occur in ~60-70% of SLE patients at some time in their disease
Very high titres are often associated with more severe disease, including renal or central nervous system involvement.
Useful in disease monitoring
an increase in antibody titre is associated with disease activity and may precede disease relapse.

Final confirmation may be done with staining of Crithidia luciliae (dsDNA in kinetoplast)

99
Q

Anti-ENA antibodies

A

Ro, La, Sm, RNP (all are ribonucleoproteins)
Antibodies may occur in SLE
Anti-Ro and La are also characteristically found in Sjogren’s syndrome
Titres not helpful in monitoring disease activity

NB: ENA = extractable nuclear antigens

100
Q

Complement profiles in SLE

A

Healthy: normal C3 and C4
Active disease: normal C3 and low C4
Severe active disease: low C3 and C4

101
Q

Inflammatory markers in SLE

A

usually ESR raised but CRP not/mildly raised
(if CRP markedly elevated, consider co-existing infection)

102
Q

Anti-phospholipid syndrome

A

Recurrent venous or arterial thrombosis

Recurrent miscarriage

May be associated with livedo reticularis, cardiac valve disease

May occur alone (primary) or in conjunction with autoimmune disease (secondary)

commonest treatable cause of recurrent miscarriages

103
Q

Anti-phospholipid antibodies

A

Three immunology/haematology tests

Anti-cardiolipin antibody:
- Antibody specific for negatively charged phospholipids

Anti-beta 2 glycoprotein 1 antibody:
- Antibody specific for glycoprotein found associated with negatively charged phospholipids

Lupus anti-coagulant:
- Antibody to phospholipid results in prolongation of phospholipid-dependent coagulation tests in vitro. Clotting time corrects/shortens with addition of excess phospholipids
- cannot be assessed if the patient is on anticoagulant therapy

104
Q

Primary Sjogren’s syndrome

A

Inflammatory infiltration and destruction of exocrine glands

Particular involvement of lacrimal glands (dryness of eyes) and salivary glands (dryness of mouth)

Dry eyes (give eyedrops)
Dry mouth (encourage fluid intake)
Arthralgias
Fatigue
Increased risk of certain lymphomas – eg MALT lymphoma (due to B-cell activation)

105
Q

Sjogren’s antibodies

A

Anti-nuclear antibody positive

Speckled staining
ENA+ve: Ro and/or La antibody positive

Anti-Ro and Anti-La may cross react with foetal cardiac conduction tissue and cause neonatal heart block or neonatal rash

106
Q

Systemic sclerosis

A

2 forms:

Limited Cutaneous Systemic Sclerosis (CREST)
Skin involvement does not progress beyond forearms,(although it may involve peri-oral skin)

Calcinosis
Raynauds
Oesophageal dysmotility
Sclerodactyly
Telangectasia

Primary pulmonary hypertension

Diffuse Cutaneous Systemic Sclerosis
Skin involvement does progress beyond forearms

- CREST features
- More extensive gastrointestinal disease
- Interstitial pulmonary disease
- Scleroderma kidney / renal crisis
107
Q

Systemic sclerosis antibodies

A

ANA = important prognostic indicator

Limited: anti-centromere antibodies
Diffuse: Anti-topoisomerase antibodies (Scl70) (Nucleolar pattern, RNA polymerase, Fibrillarin)

108
Q

Idiopathic inflammatory myopathy

A

Dermatomyositis
Within muscle – perivascular CD4 T cells and B cells
Immune complex mediated vasculitis

Polymositis
Within muscle – CD8 T cells surround HLA Class I expressing myofibres
CD8 T cells kill myofibres via perforin / granzymes

Weakness
Malaise
Rash (heliotrope)

109
Q

Immune-mediated Myositis antibodies

A

Positive ANA (in some patients)
– request extended myositis panel

Examples:

Anti-Ro antibody

Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic)
(anti-synthetase syndrome)

Anti-signal recognition peptide (SRP) antibody
(nuclear and cytoplasmic) (necrotising myositis)

Anti-TIF 1 gamma (malignancy)

Anti-PM/Scl (ILD, scleroderma overlap)

110
Q

Systemic vasculitis - ANCA associated

A

small vessel vasculitis associated with ANCA (anti-neutrophil cytoplasmic antibody): (3 types)

Microscopic polyangiitis / Microscopic polyarteritis / MPA

Granulomatosis with polyangiitis / Wegener’s granulomatosis / GPA

Eosinophilic granulomatosis with polyangiitis / Churg-Strauss syndrome / eGPA

111
Q

ANCAs

A

Antibodies specific for antigens located in primary granules within
cytoplasm of neutrophils

Inflammation may lead to expression of these antigens on cell surface of neutrophils

Antibody engagement with cell surface antigens may lead to neutrophil activation (type II hypersensitivity)

Activated neutrophils interact with endothelial cells causing damage to vessels - vasculitis

112
Q

c-ANCA vs p-ANCA

A

cANCA
Cytoplasmic fluorescence
Associated with antibodies to enzyme proteinase 3
Occurs in > 90% of patients with granulomatous polyangiitis with renal involvement

p-ANCA
Perinuclear staining pattern
Associated with antibodies to myeloperoxidase
Less sensitive and specific than cANCA
Associated with microscopic polyangiitis and eosinophilic granulomatous polyangiitis

113
Q

Th2 immune responses

A

Not fully understood in humans

Defects in skin epithelial barrier (atopic dermatitis) are a significant risk factor for development of IgE antibodies.

Initiation of allergic responses poorly understood: postulated that DC detect distress signals secreted from epithelial cells or process and present allergen to activate pro-CD4 T cell in lymph nodes.

Stressed or damaged epithelial cells secrete IL-25, IL-33, GM-CSF and TSLP which act on type 2 innate lymphoid cells which secrete Type 2 cytokines (IL-4, IL-5, IL-9, IL-13)

IL-25, IL-33, GM-CSF and TSLP promote differentiation of pro-CD4 T cell to mature CD4 Th2 cytokine producing (IL-4, IL-5 ,IL-13) cells

IL-4 plays a crucial role in development of Th2 immune responses and is only induced following peptide-MHC presentation to naïve/memory Th2 cells

IgE is the characteristic antibody of allergic sensitisation

Rapid onset of symptoms within 2hours caused by release of inflammatory mediators following allergen cross linking of IgE on surface of mast cells and basophils

Delayed symptoms result from CD4Th2 cell cytokine secretion (IL-4, IL-5, IL-13) and eosinophilic related tissue damage

Th2 cytokines secreted by tissue lymphocytes act on effector cells (eosinophils, basophils, epithelial cells, B cells, sensory neurons endothelium and smooth muscle cells) to eliminate and expel pathogens allergens, and repair tissue damage

114
Q

Diagnosis of allergic diseases

A

History is the key to diagnosis

Examination

Allergen specific IgE (Sensitisation) Tests
Skin prick and intradermal test
IgE blood tests

Functional allergen tests:

In vitro tests
Basophil activation
Serial mast cell tryptase

Ex vitro tests
Open or blinded allergen challenge

115
Q

Age of onset of allergic diseases

A

Infants:
Atopic dermatitis
Food allergy (milk, egg, nuts)

Childhood:
Asthma (HDM, pets)
Allergic rhinitis (HDM, grass, tree pollens)

Adults:
Drug allergy
Bee allergy
Pollen food allergy syndrome
Occupational allergy

116
Q

Clinical features of IgE-mediated allergic responses

A

At least 2 organ systems are usually involved.

Reproducible: occurs after every exposure

Allergic symptoms may be triggered by cofactors such as exercise, alcohol, NSAID and in children viral infection

Link between exposure and onset symptoms may not be obvious
House Dust mite
Fungal and Staph skin colonisation
Red meat ingestion

Clinical history is used to select what allergens should be tested by skin prick and/or blood tests

117
Q

Skin prick test

A

Expose patient to standardised solution of allergen extract through a skin prick to the forearm.

Use standard skin test solutions and positive control (histamine) and negative control (diluent)

Measure local wheal and flare response to controls and allergens

IgE crosslinking on skin mast cells, leading to degranulation and release of histamine and other inflammatory mediators

A positive test is indicated by a wheal ≥ 3mm greater than the negative control.

High positive and negative predictive and positive skin for aeroallergens

Allergen extracts labile for some fruit and vegetables: : prick-prick test: food and SPT

Antihistamines and some anti-depressants should be discontinued for at least 48 hours beforehand

118
Q

Intradermal allergy tests

A

Application of positive, negative controls and allergens into the skin

Moe sensitive but less specific than SPT

Best used to follow up negative venom and drug allergy test (better than blood tests)

Can be used if SPT to allergen is negative but convincing history

Labour intensive, greater risks of anaphylaxis

119
Q

IgE antibody blood tests

A

Detection of IgE to whole allergen extract or to individual protein (component) with in an allergen extract

Automated assays with excellent technical performance which can detect individual or multiple allergens

Limitation includes
Detection of IgE antibody with little clinical relevance
Allergen in low abundance may lead to reduced sensitivity
Clinical utility and cost of multiplex assay remain to be determined
Limited understanding of their role in diagnosis of allergic disorder outside of allergist/immunology specialists

120
Q

Component resolved diagnostics (CRD)

A

Abundance and stability of individual protein within allergen extract can contribute to risk of allergic disease

CRD: Test for IgE sensitisation against individual protein within whole allergen extract

Diagnostic use

Food allergy (nuts, egg, milk)

Insect allergy (wasp and bees)

Guide to immunotherapy (grass and HDM)

121
Q

Mast cell tryptase test

A

(biomarker of anaphylaxis)
Tryptase: pre-formed protein found in mast cell granules

Systemic degranulation of mast cells during anaphylaxis results in increase in serum tryptase

Peak concentration at 30 min-2 hours after on set of reaction ; returns to baseline by 6-12 hours

Failure to return to baseline after anaphylaxis may be indicative of systemic mastocytosis and hereditary alpha tryptasaemia

Useful if diagnosis of anaphylaxis is not clear (hypotension + rash during anaesthesia)

Reduced sensitivity for food induced anaphylaxis

122
Q

Challenge tests

A

Gold standard for food and drug allergy diagnosis

Increasing volumes of the offending food/drug are ingested

Double blind placebo or open challenge

Food challenges take place under close medical supervision. Very expensive in terms of clinical staff time.

Can be difficult to interpret mild symptoms

Risk of severe reaction

123
Q

Anaphylaxis

A

Anaphylaxis: several different definitions however all emphasise;
Acute onset of symptoms and/or signs ( minutes to 2-4hours)
Severe/life threatening ABC problems
Skin and mucosal symptoms and signs ( can be absent 10-20% of cases)

Clinical features
Skin (hives, itch, swollen lips, tongue, uvula) is most frequent organ involved (84%),
Cardiovascular compromise (collapse, syncope, incontinence symptoms, drop in BP) (72%)
Respiratory compromise (SOB, wheeze, stridor, fall in PEF, hypoxemia in 68%.

Respiratory symptoms occur more often in children and cardiovascular in adults

124
Q

Anaphylaxis treatment

A

IM Adrenaline

α1 receptors: causes peripheral vasoconstriction, reverses low BP and mucosal oedema

β1 receptor: increases heart rate and contractility and BP

β2 receptor: relaxation of bronchial smooth muscle and reduces release of inflammatory mediators from mast cells/basophils

Referral to an allergy/immunology clinic

Investigate the cause of anaphylaxis

Written information sheet on the following;

Recognition of symptoms
Avoidance of identifiable triggers
Indications for self treatment with an Epipen

Prescription of emergency kit to manage anaphylaxis

Copy of management plan and training for patient, carers, school staff and GP

125
Q

Foods associated with allergy

A

Although any food can trigger an allergic reaction: 8-10 foods are implicated in more than 90% cases

Peanuts, Tree nuts ( hazelnut, walnuts cashew) Shellfish, Fish, Soy, Sesame, Milk, Eggs Wheat

Most children outgrow milk and egg allergy but rarely outgrow peanut and tree nut allergy

Moderate/severe atopic dermatitis is an important risk factor for food allergy ( ?? indication for allergy testing even in absence of clinical history)

126
Q

Food allergy investigations

A

Clinical history is used to estimate prior probability of allergy, identify culprit foods and decide what diagnostic allergen tests are used to achieve a post test probability of allergy

A positive SPT/specific IgE blood test is useful to confirm a clinical history of food allergy.

A negative SPT/specific IgE blood test essentially excludes IgE mediated allergy (Negative predictive value NPV = 95%).

Fruit and vegetable skin prick test solutions are labile and it often better to useful use actual fruit or vegetable.

Testing for individual allergen protein component can distinguish between IgE sensitisation and IgE mediated allergy

A positive skin test or food specific IgE blood test indicates sensitisation but not necessarily allergy

Increasing high food-specific IgE levels or larger skin tests wheal size indicate a higher chance of allergy

Results can be followed over time to monitor for allergy persistence or resolution

IgE concentrations and SPT wheal sizes to determine presence/absent allergic disease and/or disease persistence/resolution vary with age, hospital and different blood test assays.

Gold standard for the diagnosis of food allergy is a double blind oral food challenge.

127
Q

Food allergy management

A

Avoidance
Education about food labelling, interaction with restaurants, school
Nutritional input for dietary balance, growth in children
Acknowledge anxiety, potential bullying: mental health support if needed

Emergency management
Anaphylaxis guidelines
Ensure allergic asthma is well controlled

Prevention
Breast feeding: strong family of allergy
LEAP study: early rather than delayed introduction of peanut in high risk children (moderate/severe AD and egg allergy) significantly reduces development of peanut IgE sensitisation and allergy

128
Q

Primary nut allergy (IgE-mediated)

A

Affects over 2% of children and 0.5% of adults: usually presents in the first five years of life after first exposure to nuts

Nature of symptoms is often related to site and amount of exposure: ingestion of large quantities usually leading to more severe reactions

Tree nuts (such as brazil or cashew) cause symptoms of airway narrowing more often than peanut, and cashew nut is associated with more severe reactions.

Investigation SPT, component allergen test in allergy clinics: management dependent on symptoms (see anaphylaxis and food allergy guidelines)

129
Q

Pollen food allergy syndrome (PFAS) - IgE mediated

A

PFAS affects 2% of the UK population; 40% of children and 70% of adults with IgE birch pollen antibodies have PFAS.

Sensitisation to inhalant pollen proteins lead to cross reactive IgE responses in stone fruits (apples, pears) vegetable (carrots), tree nuts (hazelnut, walnut) and peanuts

Immediate onset of symptoms (2-15min) limited to oral cavity after ingestion of raw but not cooked/processed foods; heat and protease sensitive allergens:

Management ( spit out food, take anti-histamine, avoidance, education)

1-2% cases associated with more reactions anaphylaxis: need referral and investigation

130
Q

Methods of boosting the immune response

A

Vaccination
Replacement of missing components
Blocking immune checkpoints
Cytokine therapy

131
Q

Adaptive immune response

A

B cells and T cells

Wide repertoire of antigen receptors
- Receptor repertoire is not entirely genetically encoded
- Genes for segments of receptors are rearranged and nucleic acids deleted/added at the sites of rearrangement almost randomly
- Potential to create in order of 1011 to 1012 receptors
- Autoreactive cells are likely to be generated
- Mechanisms must exist to delete or tolerise these autoreactive cells

Exquisite specificity
- able to discriminate between very small differences in molecular structure

Clonal expansion following exposure to antigen
T cells with appropriate specificity will proliferate and differentiate into effector cells (cytokine secreting, cytotoxic)
B cells with appropriate specificity will proliferate and
differentiate to T cell independent (IgM) (memory and) plasma cells
undergo germinal centre reaction and differentiate to T cell dependent IgG/A/E(M) memory and plasma cells
Plasma cells secrete high affinity specific antibodies

Immunological memory
Pre-formed pool of high affinity specific antibodies
Residual pool of specific T and B cells with enhanced capacity to respond if re-infection occurs

132
Q

Antigen presenting cells

A

APCs are cells that can present peptides to T lymphocytes to initiate an acquired immune response

These cells include:
Dendritic cell
Macrophage
B lymphocyte

Macrophages include Langerhans cells, mesangial cells,
Kupffer cells, osteoclasts, microglia etc

133
Q

T cell response

A

Antigen presented by APC to T cell with specific receptor

Clonal expansion and cytokine release

Death by apoptosis and memory cells survive

134
Q

T cell memory

A

Longevity
Memory T cells are maintained for a long time without antigen by continual low-level proliferation in response to cytokines

Different pattern of expression of cell surface proteins involved in chemotaxis / cell adhesion
These allow memory cells to access non-lymphoid tissues, the sites of microbial entry.

Rapid, robust response to subsequent antigen exposure
There are more memory cells
These cells are more easily activated than naïve cells

135
Q

B cell response

A

specific antigen presented to B cell

cytokine release

T follicular helper cells provide help (CD40L, cytokines) to B cells for expansion and isotype switching

GC dependent plasma cell secreting high affinity antibody and GC dependent memory B cells

GC independent plasma and memory cells released also

136
Q

B cell memory

A

Pre-formed antibody
Circulating high affinity IgG antibodies

Longevity
Long lived memory B cells and plasma cells

Rapid, robust response to subsequent antigen exposure
Memory B cells are more easily and rapidly activated than naïve cells

137
Q

Influenza vaccine

A

For influenza although CD8 T cells control the virus load it is antibody which provides a protective response

Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies.

138
Q

TB vaccine

A

BCG – bacilli Calmette-Guerin
Attenuated, strain of bovine tuberculosis
Some protection against primary infection
Some protection against progression to active TB

T cell response is important in protection

139
Q

Types of vaccines

A
  1. Live vaccines
  2. Inactivated/Component vaccines
    - Conjugates+ Adjuvants increase immunogenicity
  3. RNA vaccines
  4. Adenoviral vector vaccines
  5. Dendritic cell vaccines
140
Q

Live attenuated vaccines

A

Use a live organism to induce an immune response

Modified, (attenuated) organism to limit pathogenesis

Examples:

MMR
BCG

Yellow fever

Typhoid (oral)
Polio (Sabin oral)

Influenza (Fluenz tetra for children 2-17 years)

141
Q

Live vaccines pros and cons

A

Pros:
Establishes infection – ideally mild symptoms
Raises broad immune response to multiple antigens – more likely to protect against different strains
Activates all phases of immune system. T cells, B cells – with local IgA, humoral IgG
May confer lifelong immunity, sometimes just after one dose

Cons:
Possible reversion to virulence (recombination, mutation).
Vaccine associated paralytic poliomyelitis (VAPP, ca. 1: 750,000 recipients)

Spread to contacts
Spread to immunosuppressed/immunodeficient patients

Storage problems

142
Q

Inactivated / component vaccines

A

Inactivated Vaccines
Influenza (inactivated quadrivalent), Cholera, Bubonic plague, Polio (Salk), Hepatitis A, Pertussis, Rabies.

Component/subunit vaccines
Hepatitis B (HbS antigen), HPV (capsid), Influenza (recombinant quadrivalent - less commonly used)

Toxoids (inactivated toxins)
Diphtheria, Tetanus.

143
Q

Inactivated / component vaccines pros and cons

A

Pros:
No risk of reversion to virulent form
Can be used with immunodeficient patients
Storage easier
Lower cost

Cons:
Often do not follow normal route of infection

Some components have poor immunogenicity

May need multiple injections

May require modification to enhance immunogenicity
conjugate to protein carrier
adjuvant

144
Q

Conjugate vaccines

A

(to enhance T cell immunity)
(often used in children)
Polysaccharide plus protein carrier
Polysaccharide alone induces a T cell independent B cell response – transient
Addition of protein carrier promotes T cell immunity which enhances the B cell/antibody response

Haemophilus Influenzae B
Meningococcus
Pneumococcus (Prevenar)

145
Q

Adjuvant vaccines

A

(to stimulate innate immunity)

Adjuvant increases the immune response without altering its specificity
Mimic action of PAMPs (pathogen associated molecular patterns) on TLR (toll-like receptors) and other PRR (pattern recognition receptors)

Aluminium salts (humans)
Lipids – monophosphoryl lipid A (humans HPV)
Oils -Freund’s adjuvant (animals)

146
Q

mRNA vaccines

A

(SARS-CoV)

Covid virus has characteristic ‘spike proteins’ which bind to ACE2 to allow infection of cells

Infect E coli with plasmids containing DNA for spike protein
Harvest plasmids from the cultures

Excise DNA and transcribe to mRNA

Complex with lipids to
create the vaccine

Inject mRNA/lipid complexes
Non-infectious
Non-integrating
Degraded within days

mRNA enters cells ( eg muscle cells, endothelial cells, fibroblasts, dendritic cells)

mRNA translated and spike protein synthesised / expressed on surface

Stimulates immune response including B cells/antibodies and T cells

147
Q

Dendritic cell vaccines

A

Acquired defects in DC maturation and function associated with some malignancy suggests a rationale for using ex vivo–generated DC pulsed with tumour antigens as vaccines

Focus on tumour associated antigens or mutational antigens

148
Q

Adenoviral vector vaccines (SARS-CoV-2)

A

DNA of relevant protein (Covid spike protein)
inserted to viral vector
to produce vaccine

AZ Covid vaccine vector:
ChAdOx1-S

Sputnik Covid vaccine vector:
Adenovirus types 26 and 5

Infect cells in vivo

Transcription/translation to produce protein

Stimulates immune
response including B cells/antibodies and T cells

149
Q

Dendritic cell vaccines – Sipuleucel-TProvenge

A

Personalised immunotherapy for prostatic cancer
Remove white cells from patient’s blood (leukaphoresis)
APCs are harvested and incubated with recombinant protein PAP-GMCSF
Prostatic acid phosphatase-granulocyte macrophage colony stimulating factor
APCs infused back to patient
Stimulates patient’s immune response

150
Q

Replacement of missing components of immune system

A

Haematopoietic stem cell transplantation
Donor or autologous
Indications
Life-threatening primary immunodeficiencies
Severe combined immunodeficiency
Leukocyte adhesion defect
Haematological malignancy etc
Offers potential for complete and permanent cure

151
Q

Antibody replacement

A

Human normal immunoglobulin
Prepared from pools of >1000 donors
Contains preformed IgG antibody to a wide range of unspecified organisms
Blood product:
Donors screened for Hep B, Hep C and HIV
Further treated to kill any live virus
Administration
IV or SC

152
Q

Indications for antibody replacement therapy

A

Primary antibody deficiency
X linked agammaglobulinaemia
X linked hyper IgM syndrome
Common variable immune deficiency

Secondary antibody deficiency
Haematological malignancies
- Chronic lymphocytic leukaemia
- Multiple myeloma
After bone marrow transplantation

153
Q

Specific Igs used for antibody replacement therapy

A

Human immunoglobulin used for post-exposure prophylaxis (passive immunisation)

Derived from plasma donors with high titres of
IgG antibodies to specific pathogens

Hepatitis B immunoglobulin – needle stick/bite/sexual contact – from HepBSag+ve individual
Rabies immunoglobulin – to bite site following potential rabies exposure
Varicella Zoster immunoglobulin – women <20 weeks pregnancy or immunosuppressed where aciclovir or valaciclovir is contraindicated
Tetanus immunoglobulin – no specific preparation available in UK – use IVIG for suspected tetanus

154
Q

Adoptive cell transfer using T cells

A

Virus specific T cells

Tumour infiltrating T cells (TIL – T cell therapy)

T cell receptor T cells (TCR - T cell therapy)

Chimeric antigen receptor T cells (CAR – T cell therapy)

155
Q

Virus specific T cell therapy

A

EBV related B cell lymphoproliferative disease

Severe persistent viral infection in immunocompromised

156
Q

Tumour infiltrating lymphocyte (TIL) T cell therapy

A

Tumour excision

Tumour fragments grown with IL-2

selected and expanded

TIL infusion & Lymphoid depletion

157
Q

CAR T cell therapy

A

T cells from peripheral blood

Viral or non-viral insertion of genes into T cells

activation of T cell receptor and chimeric antigen receptor

expand TCR gene-engineered cells

Cells infused with IL-2

Used for:
Acute lymphoblastic leukaemia
Non-Hodgkin lymphoma
CAR T cells less successful in solid tumours

158
Q

Blocking immune checkpoints

A

Pembrolizumab and Nivolumab: Antibodies specific for PD-1 (blocking T cell programmed cell death, used in melanoma and metastatic renal cell cancer))

Ipilimumab: Antibody specific for CTLA4 (allows T cell activation through inhibiting interaction with CD80 and CD86, used in melanoma)

159
Q

Cytokine therapy

A

Aim
Modify immune response

Examples

Interleukin 2 – stimulate T cell response
Renal cell cancer

Interferon alpha 2a – immunomodulatory effect
Behcet’s

Interferon alpha – antiviral effect
Hepatitis B
Hepatitis C (with ribavirin)

Interferon gamma – enhance macrophage function
Chronic granulomatous disease

160
Q

Methods of suppressing the immune response

A

Steroids
Anti-proliferative agents
Plasmapheresis
Inhibitors of cell signalling
Agents directed at cell surface antigens
Agents directed at cytokines and their receptors

161
Q

Corticosteroids

A

Synthetic glucocorticoids
Based upon naturally occuring steroids
No mineralocorticoid activity
Prednisolone in Europe
Prednisone in USA (metabolised into prednisolone)
metabolised by liver into prednisolone
Endogenous secretion equivalent to 3-4 mg prednisolone

Used in:
Allergic disorders
Auto-immune disease
Auto-inflammatory diseases
Transplantation
Malignant disease

162
Q

Actions of corticosteroids

A

Effects on prostaglandins:
Phospholipase A2
- Breaks down phospholipids to form arachidonic acid which is converted to eicosanoids (eg prostaglandins, leukotrienes) by cyclo-oxygenases
Corticosteroids inhibit phospholipase A2
- Blocks arachidonic acid and prostaglandin formation and so reduces inflammation

Effects on phagocytes:
Decreased traffic of phagocytes to inflamed tissue
Decreased expression of adhesion molecules on endothelium
Blocks the signals that tell immune cells to move from bloodstream and into tissues
Results in transient increase in neutrophil counts
Decreased phagocytosis
Decreased release of proteolytic enzymes

Effects on lymphocyte function:
Lymphopenia
Sequestration of lymphocytes in lymphoid tissue
Affects CD4+ T cells > CD8+ T cells > B cells
Blocks cytokine gene expression
Decreased antibody production
Promotes apoptosis

163
Q

Side effects of corticosteroids

A

Metabolic effects:
Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression

Other effects:
Cataracts, glaucoma, peptic ulceration, pancreatitis,
avascular necrosis

Immunosuppression:
infection

164
Q

Anti-proliferative immunosuppressants

A

Drugs (selected)
Cyclophosphamide
- Mycophenolate
Azathioprine

Action
Inhibit DNA synthesis
Cells with rapid turnover most sensitive

Toxicity
Bone marrow suppression
Infection
- Malignancy
- Teratogenic

165
Q

Cyclophosphamide Side effects

A

Toxic to proliferating cells
Bone marrow depression
Hair loss
Sterility (male»female)
Haemorrhagic cystitis
Toxic metabolite acrolein excreted via urine
Malignancy
Bladder cancer
Haematological malignancies
Non-melanoma skin cancer
Infection
Pneumocystis jiroveci

166
Q

Azathioprine side effects

A

Bone marrow suppression
Cells with rapid turnover (leucocytes and platelets) are particularly sensitive
1:300 individuals are extremely susceptible to bone marrow suppression
Thiopurine methyltransferase (TPMT) polymorphisms
Unable to metabolise azathioprine
Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy
Hepatotoxicity
Idiosyncratic and uncommon
Infection
Serious infection less common than with cyclophosphamide

167
Q

Mycophenolate mofetil side effects

A

Bone marrow suppression Infection
Cells with rapid turnover (leucocytes and platelets) are
particularly sensitive
Infection
Particular risk of herpes virus reactivation
Progressive multifocal leukoencephalopathy (JC virus)

168
Q

Plasmapheresis and plasma exchange

A

Aim: removal of pathogenic antibody
Patient’s blood passed through cell separator
Own cellular constituents reinfused
Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)

Problems
Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent

169
Q

Indications for plasma exchange

A

Severe antibody-mediated disease:

Goodpasture syndrome
- Anti-glomerular basement membrane antibodies

Severe acute myasthenia gravis
- Anti-acetyl choline receptor antibodies

Antibody mediated transplant rejection/ABO incompatible
- Antibodies directed at donor HLA/AB molecules

170
Q

Calcineurin inhibitors (mechanism)

A

Calcineurin role:
T cell receptor engagement
Increased cytoplasmic calcium
binds to calmodulin
activates calcineurin
activates NFATc
upregulates expression of IL-2

Inhibit T cell proliferation/function

Used in:
Transplantation
SLE
Psoriatic arthritis

eg. ciclosporin, tacrolimus

171
Q

mTOR inhibitors

A

eg. rapamycin, sirolimus

Inhibit T cell proliferation and function through PI3K pathway

Used in:
Transplantation

172
Q

PDE4 inhibitors

A

eg. apremilast

Inhibition of PDE4 leads
to increase in cAMP

Influences gene transcription
via protein kinase A pathway

Modulates cytokine production

Effective in psoriasis and
psoriatic arthritis

173
Q

JAK inhibitors

A

Jakinibs

Inhibit JAK-STAT signalling (associated with cytokine receptors)

Influences gene transcription
Inhibits production of inflammatory molecules

Effective in Rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis

174
Q

Agents directed at cell surface antigens

A

Drugs
- Rabbit anti-thymocyte globulin (t cells)
- Basiliximab – anti-CD25 (t cells)
- Abatacept – CTLA4-Ig (t cells)
- Rituximab – anti-CD20 (b cells)
- Vedolizumab – anti-a4b7 integrin (lymphocyte migration)

Actions include
Block signalling
Cell depletion
Inhibit migration

175
Q

Anti-thymocyte globulin

A

Indications and dosing
- Allograft rejection (renal, heart)
Daily intravenous infusion

Action – multiple modes
Lymphocyte depletion
Modulation of T cell activation
- Modulation of T cell migration

Toxicity
Infusion reactions
Leukopenia
- Infection
- Malignancy

Specificities include
CD2
CD3
CD4
CD8
CD28
CD11a
HLA class I and II

176
Q

Basiliximab

A

Antibody directed at CD25 (IL-2Ra chain)

Indications and dosing
Prophylaxis of allograft rejection
Intravenous given before and after transplant surgery

Action
Blocks IL-2 induced signalling and inhibits T cell proliferation

Toxicity
Infusion reactions
- Infection
- Concern re long term risk malignancy

177
Q

Abatacept

A

CTLA4-Ig fusion protein

Indications and dosing
Rheumatoid arthritis
Intravenous 4 weekly
Subcutaneous weekly

Action
Reduces costimulation of
T cells via CD28 (through CD80 and CD86)

Toxicity
Infusion reactions
Infection (TB, HBV, HCV)
- Caution wrt malignancy

178
Q

Rituximab

A

monoclonal antibody specific for CD20

Indications and dose:
Lymphoma
Rheumatoid arthritis
SLE
2 doses intravenous every 6-12 months (RA)

Action:
Depletes mature B cells

Toxicity:
Infusion reactions
Infection (PML)
Exacerbation CV disease

179
Q

Vedolizumab

A

acts on cell migration: antibody specific for alpha4beta7 integrin
Binds to MadCAM1 to mediate leukocyte binding to endothelium and extravasation to tissue

Indications and dosing:
Inflammatory bowel disease
Intravenous every 8 weeks

Action:
Inhibits leukocyte migration

Toxicity:
Infusion reactions
Hepatotoxic
Infection (? PML)
Concern re malignancy

180
Q

Agents directed at cytokines and their receptors (targets)

A

TNF alpha
IL-1
IL-6
IL-17/23 pathway
IL-4/5/13 pathways
RANK pathway

181
Q

TNF alpha

A

pivotal cytokine in inflammation in many conditions

activates fibroblasts, t cells, b cells, monocytes, osteoclasts etc.

blockade used in Rheumatoid arthritis, Psoriasis and psoriatic arthritis, Inflammatory bowel disease, Familial Mediterranean fever

182
Q

anti-TNFalpa antibodies

A

Infliximab, Adalimumab, Certolizumab, Golimumab

Indications and dosing
- Rheumatoid arthritis
- Ankylosing spondylitis
- Psoriasis and psoriatic arthritis
Inflammatory bowel disease
- Subcutaneous or intravenous

Action
- Inhibit TNFa

Toxicity
Infusion or injection site reactions
- Infection (TB, HBV, HCV)
Lupus-like conditions
Demyelination
- Malignancy

183
Q

Etanercept

A

TNFalpha antagonist

Indications and dosing
- Rheumatoid arthritis
- Ankylosing spondylitis
Psoriasis and psoriatic arthritis
- Subcutaneous weekly

Action
- Inhibits TNFa and TNFb

Toxicity
Injection site reactions
Infection (TB, HBV, HCV)
Lupus-like conditions
Demyelination
- Malignancy

184
Q

IL-1 and inflammasome

A

IL-1 secretion driven via the inflammasome

IL-1 blockade may be used in Familial Mediterranean Fever, Gout, Adult Onset Stills Disease

185
Q

IL-6 receptor antibodies

A

Tocilizumab, Sarilumab

IL-6 acts on t cells, b cells, macrophages and synoviocytes

Indications and dosing:
Castleman’s disease
Rheumatoid arthritis
Subcutaneous every 1-2 weeks

Action:
Reduces macrophage, T cell,
B cell, neutrophil activation

Toxicity:
Infusion reactions
Infection
Hepatotoxic
Elevated lipids
Caution wrt malignancy

186
Q

IL-23 and IL-17 pathway

A

IL23 – IL17 pathway important in spondyloarthritides and related conditions

Axial spondyloarthritis (AS), Psoriasis and psoriatic arthritis, Inflammatory bowel disease (not anti-IL17 for IBD)

activate Th17 differentiation

187
Q

Guselkumab

A

antibody vs p19 alpha subunit of IL23

  • IL-23 comprises p40+p19

Indications and dosing:
Psoriasis, psoriatic arthritis
Subcutaneous every 8 weeks

Action:
Inhibits IL-23

Toxicity
Injection site reactions
Infection (TB)
Concern re malignancy

188
Q

IL-4, IL-5, IL-13 pathways

A

IL-4, IL-5 and IL-13 are key cytokines in Th2 and eosinophil responses

IL-4/13 blockade using an antibody specific for the IL4 receptor alpha subunit may be used for eczema and asthma
Anti-IL13 antibody may be used for management of eczema
Anti-IL5 antibody is used for eosinophilic asthma

189
Q

RANK & RANK-ligand

A

RANK ligand / RANK receptor pathway important in driving osteoclast differentiation and function

Anti-RANK ligand antibody is used in management of osteoporosis

190
Q

Denosumab

A

antibody directed at RANK ligand

Indications and dosing:
Osteoporosis
Subcutaneous every 6 months

Action:
Inhibits RANK mediated osteoclast
differentiation and function

Toxicity:
Injection site reactions
Infection – mildly immunosuppressive
Avascular necrosis of jaw

191
Q

Side effects of biologic agents - reactions

A

Infusion reactions
Urticaria, hypotension, tachycardia, wheeze – IgE mediated
Headaches, fevers, myalgias – not classical type I hypersensitivity

Injection site reactions
Peak reaction at ~48 hours
May also occur at previous injection sites (recall reactions)
Mixed cellular infiltrates, often with CD8 T cells
Not generally IgE or immune complexes

192
Q

Immunosuppression side effects - infection

A

Acute infection:
- Risk often > 2 x background
- Avoid contact/wash hands etc
- Vaccination (avoid live vaccines)
- Temporarily stop immunosuppression in case of infection
- Consider atypical organisms
- Appropriate antibiotics

Chronic infection:
Tuberculosis
- History, Residence, Travel, Contacts, CXR, TB Elispot
- Prophylaxis or treatment if required

HBV and HCV
- Check Hep B core antibody pre-treatment
- Check Hep C antibody pre-treatment
- Further investigate for active virus infection if serology is positive

HIV
- Check HIV serology pre-treatment
- Balance benefits against possible risks

John Cunningham Virus (JCV)
Common polyomavirus that can reactivate
- Infects and destroys oligodendrocytes
- Progressive multifocal leukoencephalopathy
- Associated with use of multiple immunosuppressive agents

193
Q

Immunosuppression side effects - malignancy

A

Lymphoma (EBV)
Non melanoma skin cancers (Human papilloma virus)
? Melanoma

  • Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation
194
Q

Immunosuppression side effects - auto-immunity

A
  • SLE and lupus-like syndromes
  • Anti-phospholipid syndromes
  • Vasculitis
  • Interstitial lung disease
  • Sarcoidosis
  • Uveitis
  • Autoimmune hepatitis
  • Demyelination
195
Q

Influenza virology

A

spike protiens: haemagglutinin, neuraminidase

genetic material: RNA in 8 discreet segments that can reassort

196
Q

Influenza virus replication cycle

A

enters cell through endocytosis
enters nucleus and takes over machinery
drives cells to copy own genome and assemble new viruses
viruses are released and infect new cells
whole process takes 6 hours; potential to make 10,000 viruses with different mutations (evolution)

NB: obligate intracellular parasites, with avian influenza viruses, human host is incompatible so replication cycle takes longer allowing immune system to recognise and fight back

replication: polymerase
transmission: haemagglutinin

197
Q

Influenza adaptation to humans

A

Influenza polymerase adaptation to mammals can be achieved by a single amino acid change in PB2 E627K allowing influenza viruses to replicate efficiently in human cells

ANP32 proteins are host proteins co-opted by influenza virus to support virus polymerase activity
(avoids host restriction factors)

transmission is via air droplets instead of through water so requires incoming virus to penetrate mucus and infect epithelial cells

Avian influenza haemagglutinin must adapt for transmission in humans by acquiring affinity for human receptors (mutations to change alpha2-3 receptor to alpha2-6 rec)

Influenza entry is pH dependent and HA protein is pH sensitive. Concentration of respiratory secretion components might decrease pH in airborne droplets. Transmissible viruses need to be stable.

198
Q

Response to pandemics

A

Non pharmaceutical interventions
Antiviral drugs (NB: used individually not in combination)
Vaccines

199
Q

Neuraminidase inhibitors (antiviral)

A

neuraminidase stops the virus from reinfecting a cell it has already infected (by degrading the sialyic acid) as the cell will die and not support another cycle of viral replication

inhibitor: viruses exiting infected cells will rebind and enter but cell will then die so viruses stop spreading and infecting new cells

eg. oseltamivir (Tamiflu), zanamivir (Relenza)

200
Q

Baloxavir

A

new anti-influenza antiviral drugs targeting polymerase (inhibits PA endonuclease); preventing viral genome replication in host cells

201
Q

Influenza vaccines

A

in those at risk of flu complications (over 65s):
A purified fraction containing HA (haemagglutinin) and NA (neuraminidase) of an inactivated virus

In children: live attenuated virus

in some people (more expensive):
A purified HA protein expressed in insect cells

202
Q

What is a coronavirus?

A

RNA genomes, single stranded positive sense RNA, very large genomes… 30kb!
Enveloped virions. 100nm
Nidovirales- a nested set of mRNAs from one large genome

Seven coronaviruses have infected humans:

OC43, 229E, NL-63 and HKU-1 cause 20-30% common colds
SARS and MERS are zoonotic .

binds to cells via ACE2

203
Q

Where did SARS-CoV-2 come from?

A

Bats harbour hundreds of different coronaviruses, most discovered by huge sequencing exercises after SARS.
These viruses recombine.
Animals in live markets or farms can act as secondary hosts.
CoV with 96% similarity to SARS CoV2 has been found in pangolins.
CoV with 99% similarity found in bats in Laos

204
Q

Time course of SARS-Cov2 infection

A

Day 0: infected
Day 3: virus positive and infectious
Day 5: symptomatic
Day 8 (+ for weeks): virus positive not infectious OR
day 7-10: virus dissemination & immunopathology

205
Q

Dexamethasone in COVID19

A

Cheap and extensively used steroid
RECOVERY trial found Dex was effective in those receiving oxygen or ventilated.
NB: if given to those who do not require ventilatory support/O2 actually has worse prognosis (suppress immune system).
Reduced deaths in illest cohort by 1/3.
Now standard of care in UK

Most useful for people in immunopathology part of course as can suppress immune system and prevent cytokine storm

Pathology (5 decks)

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