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P1 > HI - Phase 1 > Flashcards

HI - Phase 1 Flashcards

1
Q

SLE pathophysiology

A

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
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2
Q

Common manifestations of SLE

A

Mnuemonic:

So Sorry, My Heart Rate Knows No Husband

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3
Q

Lupus autoantibodies

A

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

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4
Q

Sources of reactive oxygen species

A
  • Endogenous sources* – oxidative phosphorylation, redox reactions, antimicrobial defence
  • Exogenous sources* – stress, air pollution, alcohol, smoking, radiation, infection
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5
Q

Antioxidant systems in the body

A
  • 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
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6
Q

Overview of anaemia

A

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)
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7
Q

Investigations used for anaemia

A

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

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8
Q

Types of haemoglobin

A
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9
Q

Summary of thalassemias

A

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

  1. asymptomatic
  2. alpha thalassemia trait – mild microcytic anemia
  3. HbH disease – microcytic anemia
  4. 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
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10
Q

Autoimmune disorders of platelets, WBCs, RBCs

A

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
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11
Q

Malaria life cycle

A

Most clinically relevant causes of malaria – P. falciparum (Africa + Asia), P. vivax (Asia)

  1. Female Anopheles mosquito bites human and releases sporozoites into blood
  2. Sporozoites asymptomatically infect hepatocytes and multiply substantially
  3. Rupture of hepatocyte releases next stage of parasite into the blood where it now infects and multiplies in red blood cells, causing rupture
  4. Some gametocytes are released during this process which can be taken up by another mosquito where they reproduce and continue the cycle
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12
Q

Lymphocyte receptor diversity and clonal selection

A

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

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13
Q

Central vs. peripheral tolerance

A

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)

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14
Q

Mechanisms of autoimmunity

A
  1. Reversal of anergy due to upregulation of costimulatory molecules in inflammation
  2. Emergency reversal of tolerance to aid in fighting infection
  3. Local tissue damage releasing intracellular or immune privileged antigens
  4. Alteration of self-antigens
  5. Hypersensitivity reactions
  6. Molecular mimicry
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15
Q

Common immunopharmacological drugs

A
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16
Q

Process of red blood cell maturation + regulation

A

Erythropoiesis = process of red blood cell production

  1. Begins with common myeloid progenitor which differentiates into an erythroblast
  2. Progressive maturation with loss of most organelles and nucleus to form reticulocytes
  3. 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

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17
Q

Major functions of antibodies

A

Mneumonic: COBS

  • activation of complement cascade via the classical pathway
  • activation of B lymphocytes
  • opsonisation and enhancement of phagocytosis
  • sensitisation of mast cells
18
Q

Prevention of allergy

A
  • allergy identification and avoidance (allergy testing)
  • progressive desensitisation immunotherapy
  • pharmacotherapy – antihistamines, leukotriene receptor antagonists, corticosteroids, cromones
19
Q

Overview of leukemia

A

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
20
Q

Overview of lymphoma

A

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
21
Q

Overview of myeloproliferative disorders

A

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
22
Q

Overview of multiple myeloma

A

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

23
Q

Causes and consequences of DIC

A

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
24
Q

Process of haematopoiesis

A

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
25
Q

Common chemotherapeutic agents

A

​Mnuemonic: FAR ATM

  • Folate antagonists – methotrexate
  • Antimetabolites – 5-FU
  • Ribonucleotide reductase inhibitors – hydroxyurea
  • DNA Alkylating agents – cyclophosphamide, cisplatin
  • Topoisomerase inhibitors
  • Monoclonal antibodies
26
Q

Drugs used in myeloproliferative disorders

A

Imatinib – inhibits BCR-ABL tyrosine kinase in Philadelphia chromosome positive disease

Ruxolitinib – JAK inhibitor used in myelofibrosis and polycythemia vera

27
Q

Types of polycythemia

A
28
Q

Ann Arbor classification system

A

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

29
Q

Pathophysiology of HITS

A

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

30
Q

Inflammation + cancer

A

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

31
Q

Tumour evasion of the immune system

A

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

  1. elimination
  2. equilibrium
  3. escape

Some strategies used include alteration of antigens, antigen loss, promoting tolerance, upregulating checkpoint inhibitors

32
Q

Antithrombotic proteins

A
  • antithrombin – inactivated thrombin
  • protein C + protein S – inactivate factors 8 and 5
  • tissue factor pathway inhibitor – counteracts tissue factor 3
33
Q

Examples of bleeding disorders

A
34
Q

Examples of clotting disorders

A
35
Q

Types of bone marrow transplantation

A

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

36
Q

Overview of GVHD

A

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:

  1. graft contains competent immune cells
  2. recipient is immunologically different to donor
  3. recipient is immunocompromised an unable to destroy the graft

Presentation – skin rash, diarrhoea, vomiting, weight loss, abdominal pain, dry eyes + mouth

37
Q

Common transfusion reactions

A

FNHTR = Febrile Non-Haemolytic Transfusion Reaction

AHTR = Acute Haemolytic Transfusion Reaction

DHTR = Delayed Haemolytic Transfusion Reaction

TRALI = Transfusion Related Acute Lung Injury

38
Q

Types of bruising and common causes

A
39
Q

ABO and Rhesus blood group systems

A

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

40
Q

Haemolytic disease of the newborn

A
  1. RhD- woman has an RhD+ child, some foetal cells enter maternal circulation and trigger a sensitisation reaction with production of anti-D antibodies
  2. if the same woman has another RhD+ child, anti-D antibodies will cross into the foetus and cause haemolysis that is often fatal
  3. prevention by identifying Rhesus type and infusing anti-D antibodies before sensitisation occurs
41
Q

Examples of inherited immunodeficiency

A
  • 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
42
Q

Hodgkin’s Vs Non-Hodgkin’s lymphoma

A

P1 (30 decks)

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