CP Immunology - x6 lectures Flashcards
(148 cards)
1
Q
Define - sensitivity
A
[a/(a+c)]- measure of how good is the test in identifying people with the disease
2
Q
Define Specificity
A
[d/(b+d)]- measure of how good is the test at correctly defining people without the disease
3
Q
Define predictive value
A
[a/(a+b)]-The proportion of people with a positive test who have the target disorder
4
Q
Define predictive value
A
d/(c+d) The proportion of people with a negative test who do not have the target disorder.
5
Q
Normogram
A
probability of same finding in patients without disease
6
Q
Types of diagnosis tests
A
Non specific - inflammatory markers
Disease specific - autoantibody testing, HLA typing
7
Q
Non - specific markers of systemic inflammation
A
ESR CRP Ferritin Fibrinogen Haptoglobin Albumin Complement
8
Q
Antinuclear antibodies ANA
- origins
A
LE phenomena detected by Hargraves in 1948
dsDNA identified in 1957
Anti-SM in 1966
9
Q
Detection of dsDNA and ENA’s
A
Anti-dsDNA Crithidia luciliae assay (protosoa) Farr assay ELISA ENA’s Immunoblots Individual ELISA’s Combination of antigens >100 different antibodies described in SLE
10
Q
Rheumatoid Factor
A
Antibody (IgM, IgG or IgA) directed against the Fc portion of IgG
Commonly found in rheumatoid arthritis but not diagnostic of the diseases (sensitivity and specificity around 70%)
Can be seen with other diseases in which polyclonal stimulation of B cells is seen (chronic infections)
High titters may be pathogenic in vasculitis
11
Q
What is Anti-CCP (ACPA)
A
ACPA more specific for RA than Rheumatoid Factor (RF)
Similar Sensitivity to RF
useful prognostic marker
ACPA positive patients tend to have more severe and erosive disease
12
Q
Anti-neutrophilic cytoplasmic antibodies (ANCA)
- when 1st described
- what specific for?
A
1982
autoantibody specific for Wegeners granulomatosis
13
Q
Cytoplasmic cANCA
- what is visible under fluorescence
- what are the target antigens
A
- Granular fluorescence of neutrophil cytoplasm with nuclear sparing
PR3 (90%)
Azurocidin
Lysozyme (1%)
MPO
14
Q
Perinuclear pANCA
- what is visible under fluorescence
- what are the target antigens
A
Nucleus only
MPO (70%) Azurocidin B-glucuronidase Cathepsin G (5%)* PR3
15
Q
Clinical Utility of ANCA testing
A
histopathology = gold standard
-ve ANCA assay do no exclude AASV
+ve ANCA with no symptoms - do not continue to treat
16
Q
Autoimmune Liver disease
A
Anti-mitochondrial Ab specific for primary biliary sclerosis
Anti-smooth muscle and anti-liver/kidney/microsomal (LKS) Abs, found in autoimmune hepatitis
Antibodies detected by IF screening using rodent tissue block (oesophagus, liver and kidney) and antigen specific ELISA
17
Q
Autoantibodies - Type 1 Diabetes Melatis
A
Non pathogenic Several types: islet cell antibodies anti-GAD65 anti-GAD67 anti-insulinoma antigen 2 (IA-2) insulin autoantibodies (IAAs) Disappear with progression of disease and total destruction of β islet cells
18
Q
role of autoantibodies in diagnosis of type 1 DM
A
Disease conformation
to identify relatives and patients at risk of developing autoimmune diabetes
Negative predictive value of ICA and IAA is almost 99%
Increased risk of disease development with greater number of different autoantibodies present and younger age of patient
19
Q
Future of diagnostic testing for autoimmune diseases
A
Cytokines determination in serum
Detection of antigen specific autoimmune T and B cells
T-reg detection, ? measure of therapeutic response
Personalised medicine, genetic profiling to determine individual risk of the disease and to tailor the most appropriate therapy
20
Q
Where is the most common genetic susceptibility for autoimmune disease?
A
HLA region
21
Q
How can autoimmunity arise
A
failures in central or peripheral tolerance
22
Q
causative assoications of autoimmune diseases
A
Sex (F»M)
Age - +++ elderly
Environment - infection, trauma, smoking
23
Q
Give an example of a disease that illustrates home many complex factors are required to bring about an autoimmune inflammation
A
Rheumatoid arthritis
24
Q
how does autoimmunity cause clinical disease
A
Autorective B cells and autoantibodies Directly cytotoxic Activation of complement Interfere with normal physiological function Autoreactive T cells Directly cytotoxic Inflammatory cytokine production General inflammation and end-organ dammage
25
Characteristics of organ specific autoimmune disease
Affect a single organ
Autoimmunity restricted to autoantigens of that organ
Overlap with other organ specific diseases
Autoimmune thyroid disease is typical
26
Characteristic of systemic autoimmune disease
Affect several organs simultaneously
Autoimmunity associated with autoantigens found in most cells of body
Overlap with other non-organ specific diseases
Connective tissue diseases are typical
27
Hashimotos thyroiditis
Destruction of thyroid follicles by autoimmune process
Associated with autoantibodies to thyroglobulin and to thyroid peroxidase
Leads to hypothyrodism
28
Grave's Disease
Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody
Leads to hyperthyrodism
29
myasthenic
anti-Ach receptor block the acetylcholine receptor
| progressive muscle weakness over the course of the day
30
Pernicious anaemia
Failure of B12 absorption
Intrinsic factor inhibited by plasma cell secretion
B12 not to absorb
31
Non-specific markers of systemic inflammation
```
ESR
CRP
Ferritin
Fibrinogen
Haptoglobin
Albumin
Complement
```
32
Treatment for autoimmunity
Supportive
immunosuppression
preventative
33
Symptoms of systemic lupus erythmatosus (SLE)
```
photosensitive malar rash
multiple mouth ulcers
arthralgia
alopecia
pleural effusion
```
34
Anti-nuclear antibodies
nuclei of cells = sequestered antigen
- in SLE antibodies agains proteins and DNA in nuclei of cell created
- Anti-nuclear antibodies bind to skin cells that have been damaged by UV light
- Antinuclear antibodies and antigens = immune complex cause inflammation in ANY tissue
35
Lupus Nephritis
```
Immune complex deposition
Inflammation
Leaky glomerulus
loss of renal function
scarring
irreversible renal failure
```
36
Treatment of SLE
Immunosuppression
37
What is vasculitis
inflammation of small vessels
38
3 types of ANCA vasculitis
Microscopic Polyangiitis (MPA)
Granulomatosis with Polyangiitis (GPA)
Eosinophilic Granulomatosus with Polyangiitis (EGPA)
39
Granulomatosis with Polyangiitis
| AKA - Wegener's Granulomatosis
```
Granuloma - mass inflammed tissue
Destructive lesions in:
Nose
Sinuses
Trachea
Lung
Orbits
```
```
Polyangiitis - inflammation vessels
Inflammation of small vessels in:
Skin
Kidney
Lung
Gut
```
treatment - immunosuppression
40
Raynaud's Phenomen
Primary
- common young F
- ANA negative
- Fairly harmless
Secondary
- ANA postive
- Associated scleroderma, SLE, etc
41
```
Scleroderma
symptoms
features
internal organs involvement
testing
treatment
```
digital ulcers
lung fibrosis
skin fibrosis
raynauds
Fribrosis affects - lung, gut, kidneys
ANA - looking for anti centromere/anti Scl-70 antibodies
Immunosuppression - usually poor response
42
Connective Tissue Diseases
Immunity against ubiquious self antigens causes inflammation or fibrosis in ANY tissue
43
Define allergy and hyersensitivity
Undesirable, damaging, discomfort-producing and sometimes fatal reactions produced by the normal immune system (directed against innocuous antigens) in a pre-sensitized (immune) host.
44
How many immunopathological classifications
- coombs and gell 1963
- extended classification
4
| 5
45
Explain type 1 reaction
| e.g. pollen
```
Anaphylactic
IgE
exogenous antigen
15-30min response
basophils and eosinophil
```
46
Explain type 2 reaction
| e.g. penicillin
```
cytotoxic
IgG IgM
cell surface antigen
mins - hours response
antibody and compliment
```
Associated disease
Erythroblastosis fetalis
Goodpasture's nephritis
47
Explain type 3
| e.g. Mould
```
Immune complex
IgG, IgM
soluble antigen
3-8 hours response
complement and neutrophils
```
associated disease
- SLE
48
Explain type 4
| e.g. poison Ivy
```
delayed type
None antibody
tissues and organs antigen
48-72 hours
monocytes and lymphocytes
```
49
How do allergies develop
```
Barrier dysfunction
sensitization
changes in T cell subsets, dominated by Th2
IgE
ALLERGY
```
50
Immune response to parasitic disease
```
Increased levels of IgE
Total
Specific to pathogen – cross-reactive
Tissue inflammation with:
eosinophilia & mastocytosis
Basophil infiltration
Presence of CD4+ T cells secreting:
IL4, IL5 & IL13
```
51
hygiene hypothesis
Stimulation by microbes is protective
Epidemiological data – Increase in Allergy
Animal Models – T1DM, EAE, Asthma
Increased atopy (Asthma) after anti-parasitic Rx
Prevention of autoimmunity (Crohn’s) by infections
Pro-biotics in pregnant women
Mechanism – Th1 Th2 deviation
52
genetic influence on allergic immune response
```
Polygenic diseases
Cytokine gene cluster IL3,5,9,13
IL12R; IL4R
FceRI
IFNg; TNF
```
NOT sufficient for disease
ONLY susceptibility
53
Immune responses
| - Allergens
Antigens that initiate an IgE-mediated response
| First encounter results in innate & IgM response
54
Immune response
| - conventional immune response
Allergen requires processing
Presentation to T cells & cytokine release
Results in delineation of T-helper subsets into different types
55
IgE mediated Allergic response
```
Immunopathogenesis
IgE Ab mediated mast cell and basophil degranulation- release of preformed and de novo synthesized inflammatory mediators
Clinical features
Fast onset (15-30 min)
Wheal and flare
Late phase response
Eosinophils
Central role for Th2 T cell
```
56
Role of Th2 T cell
Multiple cytokine release
Innate inflammatory response
Drive for immunoglobulin production
57
what is the ATOPIC triad
Asthma
rhinitis
eczema
58
Allergic Rhinitis
Nasal congestoin, mucus, polyps, nasal inflammation, tonsillar and adenoidal enlargement
Perennial/seasonal
House dust mite, animal danders, pollens
Treatment - Antihistamines, nasal steroids
59
Allergic Asthma
Airway inflammation, airway constriction and hyperactivity
In childhood - Aeroallergic stimuli- house dust mite
Immediate symptoms IgE mediated
Damage to airways - late phase response
Damaged airways - Hyper reactive to allergic stimuli
60
Atopic Dermatitis
Contact - allergic/non allergic
Clinically - intense itching, blistering, weeping
House dust mite - TRIGGER
Treatment - topical steroids, moisturisers
61
Anaphylaxis
an acute potentially life threatening IgE mediated systemic hypersensitivity reaction
62
Diagnosis of anaphylaxis
```
History
Specific IgE (>0.35 KuA/L)
Skin prick test (>3mm wheal) SPT Video
Intra-dermal test
Oral challenge test – Gold standard
Basophil activation test
Component resolved diagnostics
```
63
Basophil activation test
cross-linking of membrane-bound IgE, basophils upregulate the expression of specific activation markers such as CD63, CD203c and the expression of the inhibitory receptor CD300a. The exact mechanisms that govern basophil degranulation remain elusive, but it has been demonstrated that phosphorylation of p38 MAPK exerts a pivotal role in cell activation.
64
Treatment for anaphylaxis
Antihistamine, steroids, adrenaline
Immunotherapy - for life threatening reactions, severe hayfever, animal fur
Not good - multiple allergies, food, allergic rashes
65
Food allergy
```
MAJOR FOOD ALLERGENS
Water soluble glycoproteins 10 - 60 kd
COW’S MILK
EGG
LEGUMES - PEANUT; SOYBEAN; TREE NUTS
FISH
CRUSTACEANS / MOLLUSCS
CEREAL GRAINS
```
66
clinical manifestations of food allergy
```
Gastrointestinal
vomiting, diarrhoea, oral symptoms
Respiratory (upper & lower)
rhinitis, bronchospasm
Cutaneous
urticaria, angioedema
role of food in atopic dermatitis unclear
Anaphylaxis
```
67
Pattern Recognition receptors PRR
Toll-like receptors (TLR’s), NOD-like receptoes (NLR’s), RigI-like receptors (RLR’s) C-type lectins (CLR’s), scavenger receptors
68
Antimicrobial peptides
-Defensins, -defensins, cathelin, protegrin, granulsyin, histatin, secretory leukoprotease inhibitor, and probiotics
69
Cells
Macrophages, dendritic cells, NK cells, NK-T cells, neutrophils, eosinophils, mast cells, basophils, and epithelial cells
70
Complement components
Classic and alternative complement pathway, and proteins that bind complement components
71
cytokines
Autocrine, paracrine, endocrine cytokines that mediate host defense and inflammation, as well as recruit, direct, and regulate adaptive immune responses
72
B Lymphocytes
develop potential to secret antibodies: humoral immunity
73
Killer/cyotoxic T lymphocytes
lymphocytes are able to kill. Cellular immunity
74
helper T lymphocytes
secrete growth factors (cytokines) which control immune response: Help B lymphocytes and T lymphocytes (Helper T cells are target of HIV
75
suppressor T lymphocytes
may damp down immune response
76
binding of antibodies to antigens does the following
```
Neutralizaion
agglutination of microbes
precipitation of dissolved antigens
activation of complement system
leads to cell lysis
enhances phagocytosis
```
77
Immunodeficiency
where the immune system is not effective enough to protect the body against infection
Can be argued that infection is always the result of transient immunodeficiency.
Usually secondary to the effects of external factors
Some are primary immunodeficiencies caused by genetic defects in individual components of the immune system.
The type of infection is a guide to underlying cause.
Laboratory tests confirm.
78
Acquired Immunodeficiency
Many causes; transient or long-lasting; minor or major.
Stress
Surgery/burns
Malnutrition
Cancer – especially lymphoproliferative disease
Immunosuppressive effect of drugs inc. cancer therapy
Lymphocytes
Neutrophils
79
Primary Immunodeficiency
Very rare
Extensively studied - give important clues to the working of the immune system - experiments of nature.
Often diagnosed in early childhood but can present in adult life
Recurrent infection often suggests immunological problem
80
Chronic Granulomatous disease
```
Osteomyelitis
Pneumonia
Swollen lymph nodes
Ginigivitis
Non-malignant granulomas
Inflammatory bowel disease
```
81
Defects in b cells
Lead to different degrees of loss of antibody secretion.
Usually leads to recurrent bacterial infection with pyogenic organisms.
Usually diagnosed at around 1-2 years since maternal IgG protects.
Treat with antibiotics then iv IgG For life.
Most are very serious
some less serious e.g IgA deficiency.
1 in 5-700 not severely immunodeficient
82
Primary B cell deficiencies
```
Common Variable Immunodeficiency
X-linked agammaglobulinaemia
Autosomal recessive Hyper IgM syndrome
IgA Deficiency
IgG Subclass Deficiency
Transient Hypogammaglobulinaemia of infancy
```
83
Defects in T cells
Usually more dramatic since B cells also need T cell help.
Symptoms are recurrent infection with opportunistic infections, bacteria, viruses,
Fungi (candida), protozoa (pneumocystis).
84
Defects in both B and T
Severe Combined Immunodeficiency (SCID) syndromes
Combined Immunodeficiency syndromes
Bone Marrow Transplantation curative
Gene therapy
85
Primary T cell deficiencies
Severe Combined Immunodeficiency syndromes
Adenosine Deaminase Deficiency
Purine Nucleoside Phosphorylase Deficiency
MHC Class II Deficiency
Wiskott-Aldrich Syndrome
86
Define immunomodulation
The act of manipulating the immune system using immunomodulatory drugs to achieve
a desired immune response.
A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance.
87
Name 7 mechanisms of immumodulation
```
Immunization
Replacement therapy
Immune stimulants
Immune suppressants
Anti-inflammatory agents
Allergen immunotherapy (desentization)
Adoptive immunotherapy
```
88
Define Immunomodulators
Medicinal products produced using molecular biology techniques including recombinant DNA technology
89
what are the classes of immunomodulators
Substances that are (nearly) identical to the body's own key signaling proteins
Monoclonal antibodies
Fusion proteins
90
Describe Adalimumab
Human IgG1, monoclonal Ab,
| constant human domain Fc but with human variable domain in Fab' region
91
Describe Infliximab
Chimeric mouse human IgG1 monoclonal antibody,
| human constant domain and murine variable domain
92
Describe Etanercept
Fusion Protien, Fc-TNFR3 extracellular domain,
93
Describer Cetrolizumab
humanised monovalent Fab-PEG - contains polyethylene glycol (PEG) moiety, human constant domains and human constant domains with murine variable domain
94
Define Passive Immunization
transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection
95
Problems with passive immunisation
risk of transmission of viruses
| serum sickness
96
types and uses of passive immunisation
```
pooled specific human immunoglobulin
animal sera (antitoixins and antiveninins)
```
Uses
Hep B prophylaxis
Botulism, VZV in pregnancy, diphtheria, snake bites
97
Define active immunisation
simulate development of protective immune response and immunological memory
98
What is active immunogenic material
Weakened forms of pathogens
Killed inactivated pathogens
Purified materials (proteins, DNA)
Adjuvants
99
What are problems with active immunisation
Allergy to any vaccine component
Limited usefulness in immunocompromised
Delay in achieving protection
100
What are replacement therapies and immune stimulation
-Pooled human immunoglobulin (IV or SC) Used in Rx of antibody deficiency states
-G-CSF/GM-CSF
Act on bone marrow to increase production of mature neutrophils
-IL-2 (Stimulates T cell activation- rarely used)
-α-interferon (Main use in treatment of Hep C)
-β-interferon (Used in therapy of MS)
-γ-interferon
Can be useful in treatment of certain intracellular infections (atypical mycobacteria), also used in chronic granulomatous disease and IL-12 def
101
What can be used for Immunosuppression
```
Cortocosteroids
Cytotoxic/ agents
Anti-proliferative/activation agents
DMARD’s
Biologic DMARD’s
```
102
how do corticosteroids work
Decreased neutrophil margination
Reduced production of inflammatory cytokines
Inhibition phospholipase A2 (reduced arachidonic acid metabolites production)
Lymphopenia
Decreased T cells proliferation
Reduced immunoglobulins production
103
what are the side effects of corticosteroids
```
Carbohydrate and lipid metabolism
Diabetes
Hyperlipidaemia
Reduced protein synthesis
Poor wound healing
Osteoporosis
Glaucoma and cataracts
Psychiatric complications
```
104
What are cortico steroids used for
```
Autoimmune diseases
CTD, vasculitis, RA
Inflammatory diseases
Crohn’s, sarcoid, GCA/polymyalgia rheumatica
Malignancies
Lymphoma
Allograft rejection
```
105
What are T cell targeted immunosuppression straregies
Anti- IL-2 receptors mAbs
CyA Tacrolimus
Sirolimus
Azathioprine MMF
106
What drugs target lymphocytes
Antimetabolites
- Azathioprine (AZA)
- Mycophenolate mofetil (MMF)
Calcineurin inhibitors
- Ciclosporin A (CyA)
- Tacrolimus (FK506)
M-TOR inhibitors
-Sirolimus
IL-2 receptor mABs
- Basiliximab
- Daclizumab
107
What do Calcineurin inhibitors do
CyA
Binds to intracellular protein cyclophilin
Tacrolimus (FK506)
Binds to intracellular protein FKBP-12
Mode of action
Prevents activation of NFAT
Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription
T cell effects
Reversible inhibition of T-cell activation, proliferation and clonal expansion
108
Sirloins *(rapamycin)
| how does it work
Macrolide antibiotic
Also binds to FKBP12 but different effects
Inhibits mammalian target of rapamycin (mTOR)
Mode of action
Inhibits response to IL-2
T cell effects
Cell cycle arrest at G1-S phase
109
Side effects of calcineurim / mTOR
```
Hypertension
Hirsutism
Nephrotoxicity
Hepatotoxicity
Lymphomas
Opportunistic infections
Neurotoxicity
Multiple drug interactions (induce P450)
```
110
What are the clinical uses of calcineurim/mTOR
Allograft rejection
| Autoimmune diseases
111
Antimetabolites, how do they work?
-AZA
-MMF
T and B cell effects
Inhibit nucleotide (purine) synthesis
AZA
Guanine anti-metabolite
Rapidly converted into 6-mercaptopurine
MMF
Non-competitive inhibitor of IMPDH
Prevents production of guanosine triphosphate
T and B cells effects
Impaired DNA production
Prevents early stages of activated cells proliferation
112
What does Methotrexate MTX do
| What does Cyclophosphamide
Folate anatagoinists
| Cross link DNA
113
What are the cytotoxic side effects
```
ALL
Bone marrow suppression
Gastric upset
Hepatitis
Susceptibility to infections
Cylophosphamide
Cystatis
MTX
pneumonitis
```
114
What are the clinical uses of cytotoxic drugs
AZA/MMF
Autoimmune diseases (SLE, vasulitis, IBD)
Allograft rejection
MTX
RA, PsA, Polymyositis, vasculitis
GvHD in BMT
Cyclophosphamide
Vasculitis (Wagner’s, CSS)
SLE
115
What are biologic DMARD's
- Disease modifying anti rheumatic drugs
```
Anti-cytokines (TNF, IL-6 and IL-1)
Anti-B cell therapies
Anti-T cell activation
Anti-adhesion molecules
Complement inhibitors
```
116
Anticytokines
Anti-TNF
Anti IL-6
Anti IL-1
Anti-TNF
First biologics to be successfully used in therapy of RA (5 different agents now licensed)
Used in a number of other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis)
Caution: increase risk of TB
Anti-IL-6 (Tocilizumab)
Blocks IL-6 receptor
Used in therapy of RA and AOSD
May cause problems with control of serum lipids
Anti-IL-1
3 different agents available (anakinra, rilonacept and canakinumab)
Used in treatment of AOSD and autoinflammatory syndromes
117
Rituximab
Chimeric mAb against CD20- B cell surface
First approved in ’97 for treatment of chemotherapy resistant DLCL
Many uses:
Lymphomas, leukaemias
Transplant rejection
Autoimmune disorders
118
Adoptive Immunotherapy
2 examples,
uses
```
Bone marrow transplant (BMT)
Stem cell transplant (SCT)
Uses
Immunodeficiencies (SCID)
Lymphomas and leukemias
Inherited metabolic disorders (osteopetrosis)
Autoimmune diseases
```
119
Immunomodulators for allergy
| examples
Immune suppressants
Allergen specific immunotherapy
Anti-IgE monoclonal therapy
Anti-IL-5 monoclonal treatment
120
```
allergen specific immunotherapy
indications
mechanisms
routes
side-effects
```
Indications:
Allergic rhinoconjutivitis not controlled on maximum medical therapy
Anaphylaxis to insect venoms
Mechanisms:
Switching of immune response from Th2 (allergic) to Th1 (non-allergic)
Development of T reg cells and tolerance
Routes:
SC or sublingual for aero-allergens
Side-effects:
Localised and systemic allergic reactions
121
What is Omalizumab
mAb against IgE
Used in Rx of asthma
Also useful in Rx of chronic urticaria and angioedema
May cause severe systemic anaphylaxis
122
What is Mepolizumab
mAb against IL-5
Prevents eosinophil recruitment and activation
Limited effect on asthma
No clinical efficacy in hypereosinophilic syndrome
123
Who discovered MHC
Peter Alfred Gorer
124
What is MHC
- set of genes found in all vertebrate species
- expressed at cell surface and function to present self/nonself antigens for T cell antigen receptor inspection
- highly polymorphic
- 50,000 -- 100,000 MHC on average cell
125
The Human MHC
6p21.3
3.6Mbp long
aka Human Leucocyte Antigens complex
3 regions
class 1 - HLA-A,B,C (classical antigents
Class 2 - HLA-DR,DQ,DP antigens
Class 3 - HSP70, TNF, C4A, C4B,C2,BF, CYP21
Class 1 genes 3-6kb
Class 2 genes 4-11 kb
126
Where are class 1 and class 2 antigens found
Class 1
all nucleated cells
Class 2
primarily B lymphocytes, can be inducted on T lymphocytes
Both membrane bound glycoproteins
127
```
What are Class 1 associated with
what are class 2 associated with
```
Class 1 - MHC encoded 45kb heavy chain non covalently associated with non polymorphic B2 micro globulin
Class 2 - MHC encoded 31-34 kd associated with A chain non covalently assoicated with 26-29 kd B chain
128
How is HLA inherited
Mendelian inheritance, codominant expression, all inherited antigens are displayed on cell surface - HLA phenotype
129
Why is HLA polymorphism significant
capacity of individual to mount immune response in response to antigenic challenge
130
HLA Matching
Serology - Broad
HLA-A2, A9; B27, B15, DR1, DR2
Serology - Split
HLA-A2, A23(A9); B27, B62(B15); DR1, DR15(DR2)
HLA-A2, A24(A9); B27, B63(B15); DR1, DR16(DR2)
Molecular - Low
HLA-A*02, A*23; B*27, B*15; DRB1*01, DRB1*15
HLA-A*02, A*24; B27, B*15; DRB1*01, DRB1*16
Molecular - High
HLA-A*02:01, A*23:01; B*27:01, B*15:01; DRB1*01:01, DRB1*15:01
HLA-A*02:02, A*23:02; B*27:02, B*15:02; DRB1*01:02, DRB1*15:02
131
What is sensitisation
any even which elicits a HLA direceted immune response,
pregnancy, blood transfusion, transplantation
looked for by
serum screening
cross matching
132
What is a hyper acute rejection
Activation clotting cascade, activation of complement
133
What are the innate defences of the body
Skin, interferons, compliment, lysozyme, mucous membranes,
| normal commensal flora
134
what are the classification of immunodeficiencies
congenital/primary
| acquired/secondary
135
Neutrophil defects
| Qualitative
Chemotaxis – rare, congenital, inadequate signalling, abnormality in receptors or NE movement
–Killing power - inherited, Chronic Granulomatous Disease. NE fail to mount a respiratory burst in phagocytosis. Deficient in NADPH oxidase so hydrogen peroxide not formed. At risk of Staph. aureus infections
136
Neutorphil defect
| quantitative
eg - cancer treatment, bone marrow malignancy, aplastic anaemia caused by drugs
“Neutropenic”
Esp. imp. when 50% will dvlp an infection. Highly lethal if not treated quickly with correct antibiotics – empirical therapy, >50% those with Pseudomonal infections will die in 24hrs if not treated
137
T cell deficiencies
Congenital – rare
Acquired – drugs e.g. ciclosporin after transplantation (decreases graft versus host disease and rejection), steroids
Acquired – viruses e.g. HIV
138
```
T cell deficiencies caused by opportunistic pathogens
examples
bacterial,
viral,
fungal
```
May be intracellular
BACTERIAL – Listeria monocytogenes (food), Mycobacteria – MTB, MAI
VIRAL – e.g. leukaemia and transplanted pnts - HSV, CMV (pre–emptive treatment), VZV. Serological testing, prophylaxis and treatment with e.g. aciclovir and ganciclovir
FUNGAL – e.g. Candida spp., Cryptococcus spp.
139
T cell deficience caused by Cryptoporidium pram
- route
- recovery
- treatment
– Sporozoa – oocysts shed by cattle/humans.
Faecal oral route.
Most patients recover after prolonged illness of up to 3 wks.
May take much longer in T-cell deficient pnts – if at all. Symptomatic treatment only (in most cases)
140
T cell deficiency causes by Toxoplasma gondii
- Family
- route
- presentation
Sporozoa.
Cats. Humans infected by contact with cat faeces/ or from e.g. transplanted heart with the bradyzoites present.
May present with lesion in brain and neurological signs.
(most immunocompetent pnts are asymptomatic)
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T cell deficiency causes by Stronglyoides stercoralis
- Family,
- Route
- presentation
- suspected in which patient (pnts) groups
Nematode.
Larvae penetrate skin, migrate. Normal pnts aymptomatic or rash of Larva Currens but immunocompromised get multiplication, huge invasion of tissues, eosinophilia.
May get Gram negative septicaemia as larvae move. Suspect in pnts from tropical countries or old POW pnts.
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What is hypogammaglobulinaemia
Antibody problems
Congenital - rare
Acquired – multiple myeloma, chronic lymphocytic leukaemia, burns
Usually encapsulated bacteria e.g. S. pneumoniae in the resp. tract or e.g. Giardia lamblia or Cryptosporidium in GIT
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what is complement deficiency
Hereditary, rare
Encapsulated bacteria. Need complement to help kill organisms. Earlier defect in pathway then greater no. of orgs may infect.
Classical and Alternative
e.g. C5-8 then Neisseria meningitidis is important – lysis not achieved via membrane attack complex as MAC not formed. 50-60% pnts will have 1 episode of disease in life
Frequent, serious S. pneumoniae infections as poor quality opsonisation
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Why would you need a splenectomy?
| What are the implication of a splenectomy
Spleen - source of complement and antibody producing B-cells, removes opsonised bacteria from blood.
Causes - traumatic, surgical or functional e.g. sickle cell anaemia
Streptococcus pneumoniae, Haemophilus influenzae type B, N. meningitidis, malaria
Implications
High mortality, vaccination, prophylactic penicillin, education – seek help if unwell
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Immunocompromised after organ transplantation
Liver in HCV/paracetamol OD (solid organ transplants)
Stem cells in haematological malignancy.
Anti-rejection treatment suppresses cell mediated immunity to stop effects of cytotoxic and natural killer cells. Degree of immunosuppression varies on how closely the donor and recipient are matched.
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Management of infection in immunocompromised patients
Treat the known infection – empirical, need specimens from likely site of infection to guide therapy
E.g. remove catheters
Reverse defect if possible/stop immunosuppression
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How to investigate infections
History and examination
Urgent diagnosis and treatment
Blood cultures. Occasionally bone marrow cultures
Respiratory samples – esp. induced sputa, bronchoalveolar lavage and lung biopsy. Microscopy - Gram, ZN, fungal and silver stains. Viral immunofluorescence. Bacterial culture including Legionella, TB. Fungal culture, viral culture +/- PCR. Histology.
Other samples as systems suggest e.g. urine
Serology samples (e.g. Toxoplasma spp.) +/- PCR. Aspergillus antigen +/- PCR
(surveillance cultures)
Imaging studies e.g. X ray/CT chest, MRI
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How to prevent infection in immunocompromised patients
Hand washing /aseptic technique / protective isolation / HEPA air filtration (allografts)
Vaccines (avoid live vaccines in T-cell deficient)
Prophylactic antimicrobials (e.g. penicillin, septrin, aciclovir) and passive immunoglobulin
Special diet
