B cells, Antibodies, Cryoglobulinaemias, Rituximab Flashcards
1
Q
Where do B cells (B lymphocytes) develop and mature?
A
Bone marrow
2
Q
B lymphocytes: origin of name
A
Original discovery: Bursa of Fabricus in birds
But fallacious etymology is often taught in medical schools
3
Q
Can B cells act as APCs (Antigen Presenting Cells)?
A
During maturation phases, B cells are important APCs (Antigen-presenting cells)
4
Q
When do they begin to express immuniglobulin?
A
After maturation
5
Q
What is plasma cell?
A
The terminally differentiated B cell, which is able to secrete immunoglobulin (antibody)
6
Q
What is class switching?
A
“Changing the base of the heavy chain to another”
Thus they can vary isotype
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.
8
Q
What is antibodies (or immunoglobulins)?
A
Large glycoproteins (glucose + proteins) >>> that can identify and neutralise pathogens
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)
10
Q
What is the function of hypervariable region?
A
To determine which type of unique antigen antibody will bind to
11
Q
Isotypes of antibodies (immunoglobulins) are based upon what?
A
The heavy chains that they possess
12
Q
What are the isotypes of antibody?
A
- IgG
- igA
- IgM
- IgE
- IgD
Remember, GAMED
13
Q
Structure of different types of antibodies
A
- IgG: Monomeric
- IgA: Dimeric or monomeric
- IgM: Pentameric
- IgE: Monomeric
- IgD: Monomeric
14
Q
Percentage or proportion of immunoglobulins
A
- IgG: 75%
- IgA: 15%
- IgM: 10%
- IgD: 1%
- IgE: 0.1% (0.002% of Abs)
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
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
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)
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)
19
Q
Which is the most abundant Ig (Immunoglobulin) or antibody?
A
IgG (>75%)
20
Q
Which antibody is responsible for most antibody based responses to infection?
A
IgG
21
Q
In IgG >> G means?
A
Gamma-globulin
22
Q
IgG: subclasses
A
Four sub-classes:
- IgG1
- IgG2
- IgG3
- IgG4
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)
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)
25
**Antibodies that cross placenta**
Only **IgG**
26
**Consequence of IgG deficiency**
**Recurrent bacterial infection**
27
**IgG2 deficiency results in-?**
* **Haemophilus influenzae** (recurrent infections)
* **Streptococcus pneumoniae** (even pneumovax do NOT protect)
* **Recurrent bacterial infections**
## Footnote
**(Recurrent respiratory tract infections \> sinusitis, rhinitis, cold etc. by encapsulated bacteria: haemophilus influenzae, streptococcus pneumoniae \>\>\> think first \>\>\> IgA deficiency)**
28
**Antibodies that activate complement pathway**
* **IgG, IgM activate classical complement pathway**
* **IgA can activate alternative complement pathway** (Ig**A** \>\> **A**lternative)
## Footnote
******But if only asked which Ab to activate complement pathway \>\> prefer 'IgG, IgM'**
**by their Fc portions**
**Most effecieint is IgM**
29
**Which immunoglobulin does activate complement pathway most efficiently?**
**IgM**
30
**What is first antibody isotype to respond to a new infection?**
**(1st antibody to produce during an immune response)**
**IgM**
31
**IgM: Clinical significance**
* **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)**
32
**Anti-A, Anti-B antibodies: type of immunoglobulin**
**IgM**
33
**Blood transfusion reactions: antibodies**
* **Mismatched blood transfusion reaction \>\>\> IgM**
* **Anaphylactic transfusion reaction \>\>\> IgA**
34
**Monomeric form of IgM: Site and functions**
* **Site: Surface of B lymphocytes**
* **Function: Acts as B cell receptor or sIg**
35
**Antibody that binds allergen**
**IgE**
36
**Antibody that triggers mast cell degranulation**
**IgE**
37
**Antibody that provides defence against parasite infection**
**IgE**
38
**Antibody that provides protection against arthropods**
**IgE**
39
**IgE: variation of level**
**Higher levels are normal in 2.5% population, so as lower levels** (considering 95% C.I)
40
**IgE level in patients with atopy AND in patients with acute asthmatic attack**
* **Total serum IgE is frequently increased in those with atopy**
* **But serum IgE does not rise acutely during an asthmatic attack**
41
**IgE: Common site**
* **Basophils \> & causes allergy & inflammation**
* **Mast cells \> & causes allergy & inflammation**
* **Eosinophil \> & acts against parasite & arthropods**
## Footnote
**Most IgE are tightly bound to basophils and mast cells through Fc portion**
42
**IgE: Stimulus for production**
* **Parasitic worms (helminths)**
* **Arthropods**
* **Allergens**
43
**IgE: Functions**
* **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
**IgE: Clinical significance**
* **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
**Which antibody is involved in type-I hypersensitivity and anaphylaxis?**
**IgE**
46
**What is Omalizumab?**
**A mnoclonal antibody againt IgE antibody**
47
**Indication of Omalizumab**
**Severe allergic asthma**
48
**Immunoglobulin that is produced the most**
**Secretory IgA (2-3rd of daily production)**
(But the most abundant Immunoglobulin is IgG)
49
**IgA deficiency: rate in Caucasians**
**1 in 600-700 individuals**
50
**IgA: common sites**
**Body secretions**
* **Saliva, mucous, tears, colostrum, milk**
51
**IgA: primary production site**
**MALT (Mucosal associated lymphoid tissues)**
52
**Antibody that acts as host-defence in GIT**
**IgA**
53
**Antibody that acts as host defence in respiratory tract**
**IgA**
54
**IgA: Functions**
* **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
**Respiratory tract:**
**Antibody to trigger mast cell degranulation-?**
**Antibody for host defence-?**
**Antibody to promote inflammation-?**
* **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
**Name two encapsulated bacteria**
* **Streptococcus pneumoniae**
* **Haemophilus influenzae**
57
**IgA: Clinical significance**
_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
**Patient with repeated chest and sinus infection (sinusitis, rhinitis, cold etc.) with encapculated bacteria \>\>\> what to suspect?**
**igA deficiency**
**(As it provides host defence in respiratory tract)**
59
**IgA deficiency: vaccination problem**
**Deficient response to polysaccharide-based vaccinations \>\> such as HBV and tetanus.**
60
**IgA deficiency: hazard due to presence of Anti- IgA antibodies in these patients**
* **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
**Which type of antibody isotype TTG (Tissue-transglutaminase) antibody of 'coeliac disease' is?**
**IgA**
62
**IgD: Site and Function**
* **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
**IgD: Clinical significance**
**Hyper-IgD syndrome (A rare autosomal recessive periodic fever syndrome)**
64
**Hyper-IgD syndrome: inheritance**
**Autosomal Recessive (AR)**
65
**What is hyper-IgD syndrome?**
**A periodic fever syndrome**
66
**Infection:**
## Footnote
**1. Which antibody has _the most antibody-based response_?**
**2. Which antibody does _respond to a new infection_?**
**Infection**
## Footnote
**1. Most antibody based response \>\>\> IgG**
**2. Responds to a new infection \>\>\> IgM**
67
**Antibody that is useful in serodiagnosis**
**IgM**
68
**Antibodies that are found in the surface of B lymphocytes**
* **IgD**
* **Monomeric IgM**
69
**Clinical conditions with 'high IgA level'**
* **Alcoholic hepatitis**
* **Chronic active hepatitis**
* **IgA nephropathy**
70
**Clinical conditions with "low IgA level"**
* **Autoimmune disorder**
* **Chronic diarrhoea**
* **Respiratory infection**
71
**Clinical conditions with "high IgM level"**
* **Primary bilillary cirrhosis (PBC)**
* **Waldenstrom's macroglobinaemia**
* **Infection(mainly recent)**
72
**Clinical conditions with "low IgM level"**
* **Congenital myeloma**
* **Acquired myeloma**
73
**Clinical conditions with "high IgE level"**
* **Asthma**
* **ABPA (Allergic bronchopulmonary aspergillosis)**
* **Atopic dermatitis**
* **Psoriasis**
* **Parasitic diseases**
74
**Patient with recurrent bacterial infection \>\>\> what to suspect & test?**
**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
**What is cryoglobulins?**
**Antibodies (Immunoglobulins) that precipitate out upon exposure to cold temperature**
76
**Sub-division of cryoglobulins is based upon- what?**
**Whether the cryoprecipitate is monoclonal, polyclonal, or combined**
77
**Types of Cryoglobulins**
**3 types:**
* **Type 1: monoclonal IgM cryoglobulin**
* **Type 2: mixed monoclonal/polyclonal cryoglobulin**
* **Type 3: polyclonal cryoglobulin**
78
**Type I (monoclonal IgM cryoglobulin) is seen in-?**
**Waldenstrom's macroglobulinaemia**
79
**Type I (monoclonal IgM cryoglobulin): Clinical feature**
**Hyperviscosity (Primarily)**
80
**Type 2 (monoclonal/polyclonal cryoglobulin) is seen in-?**
**Chronic infections (e.g. Hepatitis C)**
81
**Type 3 (polyclonal cryoglobulin) is seen in-?**
**Connective tissue diseases, e.g.**
**Sjogren's syndrome**
**SLE**
82
**Type 2 (mixed monoclonal-polyclonal) & Type 3 (polyclonal): Clinical features**
* **Vasculitis**
* **Palpable purpura**
* **Renal failure** (high sr.creatinine)
* **Arthritis** (positive RF)
83
**Type 2 (mixed monoclonal-polyclonal) & Type 3 (polyclonal): Common Findings**
**Rheumatoid factor (RF) positive**
84
**Cryoglobulinemia vs Cold agglutinin disease**
**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
**What is Rituximab?**
**Chimseric monoclonal antibody**
86
**Mechanism of Rituximab**
**It causes complement mediated cell lysis of cells that expresses CD20 antigen**
87
**Rituximab acts against- which CD?**
**CD20**
88
**Which cells do express CD20 antigen?**
**Immature B cells**
**Mature B cells**
Some **Memory B cells**
89
**Which cells are destroyed (lysed) by Rituximab?**
**Immature B cells**
**Mature B cells**
Some **Memory B cells**
90
**Which cells are safe from Rituximab?**
* **Haematopoietic stem cells**
* **Plasma cells**
* **Immunoglobulins are safe** (NOT depleted/destroyed by Rituximab)
91
**First indication/use of Rituximab**
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
**Later indication/use of Rituximab**
* **Rheumatoid Arthritis (RA)**
* **Systemic Vasculitis**
* **Idiopathic Thrombocytopenia Purpura (ITP)**
* **Other autoimmune diseases**
## Footnote
****Congratulations to anyone who forsaw this success and bought shares when it was first licensed in 1996
93
**Rituximab is currently in trial for-?**
**Prevention of type-I Diabetes Mellitus**
94
**Overall indications of Rituximab**
* **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**
