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Immunology > B cells, Antibodies, Cryoglobulinaemias, Rituximab > Flashcards

B cells, Antibodies, Cryoglobulinaemias, Rituximab Flashcards

1
Q

Where do B cells (B lymphocytes) develop and mature?

A

Bone marrow

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2
Q

B lymphocytes: origin of name

A

Original discovery: Bursa of Fabricus in birds

But fallacious etymology is often taught in medical schools

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3
Q

Can B cells act as APCs (Antigen Presenting Cells)?

A

During maturation phases, B cells are important APCs (Antigen-presenting cells)

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4
Q

When do they begin to express immuniglobulin?

A

After maturation

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5
Q

What is plasma cell?

A

The terminally differentiated B cell, which is able to secrete immunoglobulin (antibody)

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6
Q

What is class switching?

A

“Changing the base of the heavy chain to another”

Thus they can vary isotype

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7
Q

What is “Affinity maturation”?

A

Affinity maturation refers to the process of >>>

  • Progressive development of immunoglobulin with higher affinity to the antigen
  • Site: germinal centres of lymphoid organs
  • Time: during the evolution of the humoral response
  • Target: accomplished by hypermutation of the variable region genes.
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8
Q

What is antibodies (or immunoglobulins)?

A

Large glycoproteins (glucose + proteins) >>> that can identify and neutralise pathogens

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9
Q

Structure of antibody

A

Two basic structural units:

  • A pair of large heavy chains
  • A pair of small light chains

At the tip of the antibody structure: hypervariable region (within the variable region)

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10
Q

What is the function of hypervariable region?

A

To determine which type of unique antigen antibody will bind to

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11
Q

Isotypes of antibodies (immunoglobulins) are based upon what?

A

The heavy chains that they possess

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12
Q

What are the isotypes of antibody?

A
  • IgG
  • igA
  • IgM
  • IgE
  • IgD

​Remember, GAMED

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13
Q

Structure of different types of antibodies

A
  • IgG: Monomeric
  • IgA: Dimeric or monomeric
  • IgM: Pentameric
  • IgE: Monomeric
  • IgD: Monomeric
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14
Q

Percentage or proportion of immunoglobulins

A
  • IgG: 75%
  • IgA: 15%
  • IgM: 10%
  • IgD: 1%
  • IgE: 0.1% (0.002% of Abs)
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15
Q

Half-life of different types of immunoglobulins

A
  • IgG: 7-23days (depends on sub-class)
  • IgA: 5days (approx/aver.)
  • IgM: 5days (about)
  • IgE: 2days
  • IgD: 2.8days
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16
Q

Concentrations of different types of immunoglobulins

A
  • IgG: 5-15g/L
  • IgA: 0.5-3.5g/L
  • IgM: 0.5-4g/L
  • IgE: <250ng/L
  • IgD: higher than IgE, but less than IgG, IgA, IgM
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17
Q

Number of epitope binding sites in different types of immunoglobulin

A
  • IgG: 2 epitope binding sites (As monomer)
  • IgA: 4 epitope binding sites (As dimer)
  • IgM: 10 epitope binding sites (As pentamer)
  • IgE: 2 epitope binding sites (As monomer)
  • IgD: 2 epitope binding sites (As monomer)
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18
Q

Antibodies: daily production

A
  • Production of antibody: 3gm/day
  • 2-3rd of them is IgA (but IgG is most of the serum antibodies)
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19
Q

Which is the most abundant Ig (Immunoglobulin) or antibody?

A

IgG (>75%)

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20
Q

Which antibody is responsible for most antibody based responses to infection?

A

IgG

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21
Q

In IgG >> G means?

A

Gamma-globulin

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22
Q

IgG: subclasses

A

Four sub-classes:

  • IgG1
  • IgG2
  • IgG3
  • IgG4
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23
Q

IgG: Functions

A

By Fc portion of IgG: (functions of Fc portion of IgG)

  • Activates classical complement pathway
  • Binds to macrophage & neutrophils >>> enhanced phagocytosis of bacteria and viruses
  • Binds to NK cells >>> ADCC (Antibody dependant cytotoxicity)
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24
Q

IgG: Clinical significance

A
  • Only IgG can cross placenta and enter foetal circulation
  • IgG deficiency predisposes to recurrent bacterial infection
  • It appears lately in response to infection (initial exposure) (But appears sooner in case of repeat exposure)
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25
Q

Antibodies that cross placenta

A

Only IgG

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26
Q

Consequence of IgG deficiency

A

Recurrent bacterial infection

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27
Q

IgG2 deficiency results in-?

A
  • Haemophilus influenzae (recurrent infections)
  • Streptococcus pneumoniae (even pneumovax do NOT protect)
  • Recurrent bacterial infections

​(Recurrent respiratory tract infections > sinusitis, rhinitis, cold etc. by encapsulated bacteria: haemophilus influenzae, streptococcus pneumoniae >>> think first >>> IgA deficiency)

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28
Q

Antibodies that activate complement pathway

A
  • IgG, IgM activate classical complement pathway
  • IgA can activate alternative complement pathway (IgA >> Alternative)

​But if only asked which Ab to activate complement pathway >> prefer ‘IgG, IgM’

by their Fc portions

Most effecieint is IgM

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29
Q

Which immunoglobulin does activate complement pathway most efficiently?

A

IgM

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30
Q

What is first antibody isotype to respond to a new infection?

(1st antibody to produce during an immune response)

A

IgM

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31
Q

IgM: Clinical significance

A
  • Useful in serodiagnosis: IgM confirms recent infection
  • First to be secreted
  • Anti-A, Anti-B blood antibodies
  • Antibody in acute blood transfusion reaction (ABO or Rh incompatibility)
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32
Q

Anti-A, Anti-B antibodies: type of immunoglobulin

A

IgM

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33
Q

Blood transfusion reactions: antibodies

A
  • Mismatched blood transfusion reaction >>> IgM
  • Anaphylactic transfusion reaction >>> IgA
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34
Q

Monomeric form of IgM: Site and functions

A
  • Site: Surface of B lymphocytes
  • Function: Acts as B cell receptor or sIg
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35
Q

Antibody that binds allergen

A

IgE

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36
Q

Antibody that triggers mast cell degranulation

A

IgE

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37
Q

Antibody that provides defence against parasite infection

A

IgE

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38
Q

Antibody that provides protection against arthropods

A

IgE

39
Q

IgE: variation of level

A

Higher levels are normal in 2.5% population, so as lower levels (considering 95% C.I)

40
Q

IgE level in patients with atopy AND in patients with acute asthmatic attack

A
  • Total serum IgE is frequently increased in those with atopy
  • But serum IgE does not rise acutely during an asthmatic attack
41
Q

IgE: Common site

A
  • Basophils > & causes allergy & inflammation
  • Mast cells > & causes allergy & inflammation
  • Eosinophil > & acts against parasite & arthropods

Most IgE are tightly bound to basophils and mast cells through Fc portion

42
Q

IgE: Stimulus for production

A
  • Parasitic worms (helminths)
  • Arthropods
  • Allergens
43
Q

IgE: Functions

A
  • It binds to allergen (by Fab portion)
  • Allergic reaction
    • It binds to mast cells and basophils (by Fc portion) > Allergic reaction
  • Inflammation
    • ​(when antigen/alergen binds to cell-bound IgE) >>> It triggers mast cell degranulation >>> release of vasodilators (histamin) >>> inflammatory response
    • It enables IgG, complement proteins, leukocytes to enter the tissue >>> thus promotes inflammation >>> thus protects external mucosal surface (of respiratory tract)
  • Major defence against parasitic worms & arthropods
    • When parasites or arthropods invade >>> ​Fc portion binds to Eosinophils >>> opsonisation
44
Q

IgE: Clinical significance

A
  • It is involved in >>> Type-I hypersensitivity reactions (including anaphylaxis, allergy)
  • Omalizumab (a monoclonal antibody against IgE) is NICE-approved to be used in “severe allergic asthma”
45
Q

Which antibody is involved in type-I hypersensitivity and anaphylaxis?

A

IgE

46
Q

What is Omalizumab?

A

A mnoclonal antibody againt IgE antibody

47
Q

Indication of Omalizumab

A

Severe allergic asthma

48
Q

Immunoglobulin that is produced the most

A

Secretory IgA (2-3rd of daily production)

(But the most abundant Immunoglobulin is IgG)

49
Q

IgA deficiency: rate in Caucasians

A

1 in 600-700 individuals

50
Q

IgA: common sites

A

Body secretions

  • Saliva, mucous, tears, colostrum, milk
51
Q

IgA: primary production site

A

MALT (Mucosal associated lymphoid tissues)

52
Q

Antibody that acts as host-defence in GIT

A

IgA

53
Q

Antibody that acts as host defence in respiratory tract

A

IgA

54
Q

IgA: Functions

A
  • Important in host defense in mucose membrane (respiratory tract and GIT)
    • ​​It protects internal body surfaces exposed to the environment (by > blocking the attachment of bacteria and viruses to mucous membrane)
      • ​Secretory IgA binds to mucous and trap the microbes
  • Found in secretions (secretory component to protect it from digestive enzymes in the secretion)
55
Q

Respiratory tract:

Antibody to trigger mast cell degranulation-?

Antibody for host defence-?

Antibody to promote inflammation-?

A
  • To trigger mast cell degranulation >>> IgE
  • Host defence by >>> IgA
  • Inflammation is promoted by >>> IgE (as it enables IgG, complement proteins, leukocytes to enter the tissue)
56
Q

Name two encapsulated bacteria

A
  • Streptococcus pneumoniae
  • Haemophilus influenzae
57
Q

IgA: Clinical significance

A

SARDI

  • Selective IgA deficiency is associated with autoimmune disease (e.g. coeliac disease)
  • Anaphylactic reaction to the blood products
  • Recurrent chest and sinus infection (rhinitis, cold, sinusitis) by encapsulated bacteria
  • Deficient response to polysaccharide-based vaccinations >> such as HBV and tetanus.
  • IgA containing blood products can cause severe reaction in IgA-deficienct patients
58
Q

Patient with repeated chest and sinus infection (sinusitis, rhinitis, cold etc.) with encapculated bacteria >>> what to suspect?

A

igA deficiency

(As it provides host defence in respiratory tract)

59
Q

IgA deficiency: vaccination problem

A

Deficient response to polysaccharide-based vaccinations >> such as HBV and tetanus.

60
Q

IgA deficiency: hazard due to presence of Anti- IgA antibodies in these patients

A
  • 10-44% of patients may have anti-IgA antibodies;
  • if they are given >>> IgA-containing products such as blood, plasma or immunoglobulin >>> A Severe reaction
61
Q

Which type of antibody isotype TTG (Tissue-transglutaminase) antibody of ‘coeliac disease’ is?

A

IgA

62
Q

IgD: Site and Function

A
  • Site: Surface of B lymphocytes (along with monomeric IgM)
  • Functions:
    • A puzzle, if you find out a Nature journal paper awaits you (Pastest)
    • As B cell receptor of sIg >>> activation or supression of B lymphocytes (Hani)
    • (may play a role) in eliminating B lymphocytes generating self-reactive auto-antibodies
63
Q

IgD: Clinical significance

A

Hyper-IgD syndrome (A rare autosomal recessive periodic fever syndrome)

64
Q

Hyper-IgD syndrome: inheritance

A

Autosomal Recessive (AR)

65
Q

What is hyper-IgD syndrome?

A

A periodic fever syndrome

66
Q

Infection:

1. Which antibody has the most antibody-based response?

2. Which antibody does respond to a new infection?

A

Infection

1. Most antibody based response >>> IgG

2. Responds to a new infection >>> IgM

67
Q

Antibody that is useful in serodiagnosis

A

IgM

68
Q

Antibodies that are found in the surface of B lymphocytes

A
  • IgD
  • Monomeric IgM
69
Q

Clinical conditions with ‘high IgA level’

A
  • Alcoholic hepatitis
  • Chronic active hepatitis
  • IgA nephropathy
70
Q

Clinical conditions with “low IgA level”

A
  • Autoimmune disorder
  • Chronic diarrhoea
  • Respiratory infection
71
Q

Clinical conditions with “high IgM level”

A
  • Primary bilillary cirrhosis (PBC)
  • Waldenstrom’s macroglobinaemia
  • Infection(mainly recent)
72
Q

Clinical conditions with “low IgM level”

A
  • Congenital myeloma
  • Acquired myeloma
73
Q

Clinical conditions with “high IgE level”

A
  • Asthma
  • ABPA (Allergic bronchopulmonary aspergillosis)
  • Atopic dermatitis
  • Psoriasis
  • Parasitic diseases
74
Q

Patient with recurrent bacterial infection >>> what to suspect & test?

A

Humoral immune defect

  • B cell to any isotype of immunoglobulin defect
  • IgG is more common among them
  • IgG2 is even more common

​Test: IgG response to immunisation >>> detects specific Ab deficiency

75
Q

What is cryoglobulins?

A

Antibodies (Immunoglobulins) that precipitate out upon exposure to cold temperature

76
Q

Sub-division of cryoglobulins is based upon- what?

A

Whether the cryoprecipitate is monoclonal, polyclonal, or combined

77
Q

Types of Cryoglobulins

A

3 types:

  • Type 1: monoclonal IgM cryoglobulin
  • Type 2: mixed monoclonal/polyclonal cryoglobulin
  • Type 3: polyclonal cryoglobulin
78
Q

Type I (monoclonal IgM cryoglobulin) is seen in-?

A

Waldenstrom’s macroglobulinaemia

79
Q

Type I (monoclonal IgM cryoglobulin): Clinical feature

A

Hyperviscosity (Primarily)

80
Q

Type 2 (monoclonal/polyclonal cryoglobulin) is seen in-?

A

Chronic infections (e.g. Hepatitis C)

81
Q

Type 3 (polyclonal cryoglobulin) is seen in-?

A

Connective tissue diseases, e.g.

Sjogren’s syndrome

SLE

82
Q

Type 2 (mixed monoclonal-polyclonal) & Type 3 (polyclonal): Clinical features

A
  • Vasculitis
  • Palpable purpura
  • Renal failure (high sr.creatinine)
  • Arthritis (positive RF)
83
Q

Type 2 (mixed monoclonal-polyclonal) & Type 3 (polyclonal): Common Findings

A

Rheumatoid factor (RF) positive

84
Q

Cryoglobulinemia vs Cold agglutinin disease

A

Cold agglutinin disease is NOT related to Cryoglobulinemia (Shoud NOT be confused)

Cold agglutinin disease is a form of haemolytic anaemia (idiopathic or acquired)

Two most important causes are >>

  • Lymphoproliferative disease (e.g. Lymphoma, NHL >, HL)
  • Mycoplasma pneumonia infection
85
Q

What is Rituximab?

A

Chimseric monoclonal antibody

86
Q

Mechanism of Rituximab

A

It causes complement mediated cell lysis of cells that expresses CD20 antigen

87
Q

Rituximab acts against- which CD?

A

CD20

88
Q

Which cells do express CD20 antigen?

A

Immature B cells

Mature B cells

Some Memory B cells

89
Q

Which cells are destroyed (lysed) by Rituximab?

A

Immature B cells

Mature B cells

Some Memory B cells

90
Q

Which cells are safe from Rituximab?

A
  • Haematopoietic stem cells
  • Plasma cells
  • Immunoglobulins are safe (NOT depleted/destroyed by Rituximab)
91
Q

First indication/use of Rituximab

A

It was first developed (in 1996) as a targeted therapy for >>>

  • Diffuse large B cell lymphoma

​(In combination with CHOP: Cyclophosphamide, Hydroxydaunorubicin/Adriamycin, Oncovin/Vincristine, Prednisolone)

92
Q

Later indication/use of Rituximab

A
  • Rheumatoid Arthritis (RA)
  • Systemic Vasculitis
  • Idiopathic Thrombocytopenia Purpura (ITP)
  • Other autoimmune diseases

​Congratulations to anyone who forsaw this success and bought shares when it was first licensed in 1996

93
Q

Rituximab is currently in trial for-?

A

Prevention of type-I Diabetes Mellitus

94
Q

Overall indications of Rituximab

A
  • Diffuse large B cell lymphoma​ (In combination with CHOP))
  • Rheumatoid Arthritis (RA)
  • Systemic Vasculitis
  • Idiopathic Thrombocytopenia Purpura (ITP)
  • Other autoimmune diseases
  • In trial for >>> prevention of type-I DM

Immunology (16 decks)

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