HI - Phase 1 Flashcards
SLE pathophysiology
Type III hypersensitivity resulting from the production of autoantibodies directed against soluble nuclear antigens (DNA, histones, other proteins) which form immune complexes that deposit and cause inflammatory effects throughout the body
- underlying cause is thought to be a combination of genetic predisposition and environmental triggers e.g. infection, UV light, medications
- genetic factors thought to be involved with delayed clearance of apoptotic bodies and increased likelihood of recognising these nuclear antigens as foreign
Common manifestations of SLE
Mnuemonic:
So Sorry, My Heart Rate Knows No Husband
Lupus autoantibodies
Antinuclear antibodies (ANA): high sensitivity but low specificity as found in other AI disease
More lupus specific:
- anti-Smith: small ribonucleoproteins
- anti-dsDNA
Anti-phospholipid – usually targets proteins bound to phospholipid, less specific as well
- anticardiolipin (syphilis false positive)
- lupus anticoagulant/antibody
- anti-B2 glycoprotein 1
Can lead to antiphospholipid syndrome which causes a hypercoagulable state leading to stroke, DVT and other clotting issues
Sources of reactive oxygen species
- Endogenous sources* – oxidative phosphorylation, redox reactions, antimicrobial defence
- Exogenous sources* – stress, air pollution, alcohol, smoking, radiation, infection
Antioxidant systems in the body
- Preventative* – stop the initial formation of free radicals e.g. chelators, melanin
- Radical scavenging* – mop up free radicals e.g. enzymes, vitamins, dietary sources, melatonin
- Repair* – DNA repair enzymes
Overview of anaemia
Anemia = decrease in blood oxygen carrying capacity due to low RBCs or haemoglobin
Hb definition: <120g/L in females, <140g/L in males
Can also categorise based on mechanism:
- decreased production
- blood loss
- increased destruction (haemolysis) – intravascular (DIC, TTP, mechanical valves) or extravascular (splenic destruction e.g. malaria, sickle cell)
Investigations used for anaemia
Full blood count – diagnose anaemia, determine MCV, reticulocytes indicate compensation
Peripheral blood smear – morphology of cells provides diagnostic information
Indicators of haemolysis – LDH release from RBCs, unconjugated bilirubin, haptoglobins which decrease in number when used to clear free Hb
Types of haemoglobin
Summary of thalassemias
Thalassemias result from defective synthesis of Hb globin chains, leading to imbalances in alpha or beta chains and ineffective erythropoiesis
Alpha thalassemia
Results from deletions of one or more of the four genes that contribute to alpha chains, number of genes deleted determines severity
- asymptomatic
- alpha thalassemia trait – mild microcytic anemia
- HbH disease – microcytic anemia
- hydrops fetalis – incompatible with life
Beta thalassemia
Results from mutations in the two genes that encode beta chains
- minor: only one allele bears a mutation leading to microcytic anemia
- intermedia: both alleles are mutated but some beta globin chain production is possible
- major: homozygous mutation in which no beta globin chains are produced, raised HbF and HbA2, completely dependent on transfusion
Autoimmune disorders of platelets, WBCs, RBCs
Immune thrombocytopenic purpura (ITP):
Low platelet count resulting in bleeding tendency and bruising/purpura
- generation of autoantibodies directed against platelet membrane antigens for unclear reasons results in excessive splenic destruction
- bone marrow is normal, and no other causes of low platelets are present
Autoimmune neutropenia:
Autoantibodies directed against neutrophil surface glycoproteins causing destruction which can occur in isolation or in association with another condition
- primary – not associated with other pathology, normally in children
- secondary – due to an underlying cause such as drugs, viruses
Autoimmune haemolytic anemia:
Significantly shortened RBC lifespan due to autoantibodies (IgG or IgM) directed against membrane antigens, classified depending on the antibody type which is determined by the direct Coomb’s test which is used for AIHA diagnosis
- warm AIHA – IgG predominant, antibodies most active at normal body temperature
- cold AIHA - IgM predominant, antibodies most active below normal body temperature
Malaria life cycle
Most clinically relevant causes of malaria – P. falciparum (Africa + Asia), P. vivax (Asia)
- Female Anopheles mosquito bites human and releases sporozoites into blood
- Sporozoites asymptomatically infect hepatocytes and multiply substantially
- Rupture of hepatocyte releases next stage of parasite into the blood where it now infects and multiplies in red blood cells, causing rupture
- Some gametocytes are released during this process which can be taken up by another mosquito where they reproduce and continue the cycle
Lymphocyte receptor diversity and clonal selection
Major mechanism of lymphocyte receptor diversity production is VDJ recombination:
- somatic recombination of variation, diversity, and junctional segments
- junctional diversity due to point mutations
Clonal selection = theory of adaptive immunity, VDJ recombination produces a massive array of different lymphocyte receptors with 10-100 of each, APCs will find the cognate lymphocyte and activate causing them to undergo proliferation to produce a substantial immune response
Central vs. peripheral tolerance
Central tolerance
- T cells (thymus): double positive lymphoid progenitors are tested for binding to MHC molecules and either destroyed if binding is too strong/weak or sent down a committed pathway and tested again by medullary cells through AIRE expression
- B cells (marrow): receptors are produced via VDJ recombination and tested against self-antigens, receptor editing can occur if autoreactivity is present
Peripheral tolerance
both B and T cells in the periphery are checked for autoreactivity and can be suppressed through various mechanisms (anergy, suppression by regulatory cells, apoptosis)
Mechanisms of autoimmunity
- Reversal of anergy due to upregulation of costimulatory molecules in inflammation
- Emergency reversal of tolerance to aid in fighting infection
- Local tissue damage releasing intracellular or immune privileged antigens
- Alteration of self-antigens
- Hypersensitivity reactions
- Molecular mimicry
Common immunopharmacological drugs
Process of red blood cell maturation + regulation
Erythropoiesis = process of red blood cell production
- Begins with common myeloid progenitor which differentiates into an erythroblast
- Progressive maturation with loss of most organelles and nucleus to form reticulocytes
- Reticulocytes circulate in blood for 1-2 days before losing remaining organelles and becoming mature erythrocytes
After circulating for 120 days, senescent red blood cells are selected out and destroyed by macrophages of the reticuloendothelial system, primarily in the liver and spleen
Major regulation of this process is through the production of the endocrine hormone erythropoietin (EPO) which is secreted by the kidney in response to low oxygen in blood
Major functions of antibodies
Mneumonic: COBS
- activation of complement cascade via the classical pathway
- activation of B lymphocytes
- opsonisation and enhancement of phagocytosis
- sensitisation of mast cells
Prevention of allergy
- allergy identification and avoidance (allergy testing)
- progressive desensitisation immunotherapy
- pharmacotherapy – antihistamines, leukotriene receptor antagonists, corticosteroids, cromones
Overview of leukemia
Leukemias are malignancies of blood cells resulting from defects in the process of haematopoiesis resulting in abnormal accumulation of immature blood cells in the bone marrow, blood, and tissues
- divided into myeloid or lymphocytic depending on the cell line affected
- acute leukemias have a much faster onset and involve more immature blast cells while chronic leukemias develop over months/years from more developed cell types
Overview of lymphoma
Lymphoma = malignancy of the lymphoid system due to excessive proliferation of lymphocytes which tend to accumulate in lymphoid tissues include lymph nodes, spleen and thymus
- Originally classified as Hodgkin or non-Hodgkin although modern systems use molecular markers and cell line affected i.e. B cells, T cells, NK cells
Clinical presentation usually involves:
- lymphadenopathy – painless and rubbery
- enlargement of spleen, tonsils etc.
- specific symptoms of organ compression such as bowel obstruction, spinal compression
- constitutional symptoms
Hodgkin lymphoma
Uncommon malignancy arising from mature B cells, characterised by the presence of bilobed Reed-Sternberg cells on peripheral blood smear
- many cases associated with EBV infection, though not all and not necessarily causal
Non-Hodgkin lymphoma
All other types of lymphoma, approximately 80% are of B cell origin with a large degree of variability in epidemiology and aetiology
- B cells – diffuse large B cell lymphoma, Burkitt lymphoma (linked to EBV), follicular lymphoma, mantle cell, MALT lymphoma (linked with H. pylori)
- T cells – adult T cell lymphoma (linked to HTLV-1), mycosis fungoides
Overview of myeloproliferative disorders
Myeloproliferative neoplasms (MPN) are characterised by excessive amounts of terminally differentiated myeloid blood cells in the circulation including erythrocytes, leukocytes, and platelets
- generally Ph– and highly associated with mutations in JAK2, CALR and MPL
- typically diagnosed in people aged 50-70
Myeloproliferative neoplasms exist on a spectrum of disease, in particular:
- essential thrombocytosis and polycythemia vera can enter a spent phase and progress to secondary myelofibrosis
- all MPNs may also progress to secondary AML which has a worse prognosis than the primary disease
Overview of multiple myeloma
Multiple myeloma = malignant disease of plasma cells in the bone marrow, it is the second most common haematological cancer which primarily occurs in older people
- normally 5% plasma cells in bone marrow, this increases above 10% in MM from excessive proliferation of plasma cells stimulated by bone marrow stromal cells
- MM cells produce large amounts of abnormal antibodies called paraproteins which consist of light chains only which cause renal failure
- MM cells also decrease osteoblast activity and increase osteoclast activity resulting in lytic bone lesions and fractures
Presentation – back pain, respiratory infections, anemia, renal failure, proteinuria, bone lesions
Causes and consequences of DIC
Disseminated intravascular coagulation = syndrome in which there is systemic widespread activation of the coagulation cascade resulting in blockage and ischemia of many organs as well as bleeding tendency from consumption coagulopathy
- results from release of procoagulants that tip the balance towards haemostasis including in sepsis, malignancy, trauma, transfusion reactions
- blockage of small/medium blood vessels causes necrosis of kidney, liver, brain, lungs
Process of haematopoiesis
Haematopoiesis = process of blood cell formation, occurs primarily in the bone marrow of the axial skeleton in adults
- begins with pluripotent stem cells which can self-renew or become committed progenitor cells
- occurs in liver and spleen in utero, bone marrow disease can cause this to be reactivated which is termed extramedullary haematopoiesis
Common chemotherapeutic agents
Mnuemonic: FAR ATM
- Folate antagonists – methotrexate
- Antimetabolites – 5-FU
- Ribonucleotide reductase inhibitors – hydroxyurea
- DNA Alkylating agents – cyclophosphamide, cisplatin
- Topoisomerase inhibitors
- Monoclonal antibodies
Drugs used in myeloproliferative disorders
Imatinib – inhibits BCR-ABL tyrosine kinase in Philadelphia chromosome positive disease
Ruxolitinib – JAK inhibitor used in myelofibrosis and polycythemia vera
Types of polycythemia
Ann Arbor classification system
Staging used for Hodgkin’s lymphoma in adults + children, and non-Hodgkin’s in adults
I - involvement of one group of lymph nodes
II - two groups of lymph nodes on the same side of the diaphragm
III - groups of lymph nodes on both sides of the diaphragm
IV - involvement of extralymphatic tissues
Pathophysiology of HITS
Heparin induced thrombocytopenia syndrome (HITS) = immune mediated reaction in which platelet factor 4 released from platelet binds to heparin and forms an immunogenic complex leading to production of anti-platelet antibodies that cause aggregation and early destruction
Inflammation + cancer
An inflammatory microenvironment is often favourable to carcinogenesis due to:
- production of free radicals which can induce mutation
- release of cytokines and mediators that promote growth, angiogenesis, cell survival
e.g. TNFa, IL-1, IL-6, VEGF, MMPs, COX2
Generally, a high proportion of innate immune cells is more conducive to cancer propagation while a high proportion of adaptive immune cells, especially CTLs are associated with the anti-tumour response
Tumour evasion of the immune system
The immune system normally recognises cancer due to neoantigens or other abnormal expression, any clinically significant cancer has evaded the anti-tumour immune response which occurs in three phases
- elimination
- equilibrium
- escape
Some strategies used include alteration of antigens, antigen loss, promoting tolerance, upregulating checkpoint inhibitors
Antithrombotic proteins
- antithrombin – inactivated thrombin
- protein C + protein S – inactivate factors 8 and 5
- tissue factor pathway inhibitor – counteracts tissue factor 3
Examples of bleeding disorders
Examples of clotting disorders
Types of bone marrow transplantation
Autologous – from same person, used to increase chemotherapeutic dosages with the ability to ‘rescue’ the bone marrow afterwards with the person’s own cells
Syngeneic – from an identical twin which will be perfectly genetically matched
Allogeneic – from another person of the same species, need to be HLA matched to limit graft rejection or GVHD, stem cells typically harvested from peripheral blood after dose of G-CSF
Overview of GVHD
Condition that occurs following allogeneic haematopoietic stem cell transplant in which the donated blood cells will recognise the recipient’s body as foreign and initiate an immune response, can be acute (occurring within 100 days) or chronic (begins after 100 days)
Requires three criteria:
- graft contains competent immune cells
- recipient is immunologically different to donor
- recipient is immunocompromised an unable to destroy the graft
Presentation – skin rash, diarrhoea, vomiting, weight loss, abdominal pain, dry eyes + mouth
Common transfusion reactions
FNHTR = Febrile Non-Haemolytic Transfusion Reaction
AHTR = Acute Haemolytic Transfusion Reaction
DHTR = Delayed Haemolytic Transfusion Reaction
TRALI = Transfusion Related Acute Lung Injury
Types of bruising and common causes
ABO and Rhesus blood group systems
ABO blood grouping:
most common immunogenic antigen in blood transfusion reactions, based on presence of two carbohydrate antigens A and B on a H backbone
- inheritance pattern is multiallelic and codominant
- gives rise to four blood groups – A, B, AB, O
- almost all individuals will produce antibodies against the antigen that they lack, this is the underlying cause of transfusion reactions
Rhesus blood grouping:
complex inheritance process at two major loci – D (D, d) and CE (C, E, c, e), if an individual expresses any of the dominant antigens they will be Rhesus positive, most common Rh antibody is anti-D
Haemolytic disease of the newborn
- RhD- woman has an RhD+ child, some foetal cells enter maternal circulation and trigger a sensitisation reaction with production of anti-D antibodies
- if the same woman has another RhD+ child, anti-D antibodies will cross into the foetus and cause haemolysis that is often fatal
- prevention by identifying Rhesus type and infusing anti-D antibodies before sensitisation occurs
Examples of inherited immunodeficiency
- X-linked agammaglobulinemia – failure of B cells to mature therefore no antibody production resulting from Bruton’s tyrosine kinase mutation
- CVID – heterogenous disease of antibody deficiency with unknown cause
- Hyper-IgM syndrome – inability to undergo isotype switching
- SCID – defects in genes such as adenosine deaminase resulting in lack of B and T cells
Hodgkin’s Vs Non-Hodgkin’s lymphoma
