Humoral-Mediated Immunity - Immunology

Overview

Introduction

Humoral immunity is based upon the production and activity of antibodies that
- defend against extracellular threats such as bacteria via
  - opsonization of the surface of the pathogen leading to
    - phagocytosis by innate immune cells like macrophages
    - cytotoxicity by triggering release of toxic compounds by innate immune cells
  - neutralization of pathogens and viruses by
    - blocking interaction of pathogenic proteins with host receptors
    - inactivating virulence factors expressed by pathogens
  - activation of the complement cascade through the classical pathway
The main effector cell of humoral immunity B-cell that
- is activated by displaying peptides to helper T-cells
- undergoes affinity maturation to make higher affinity antibodies
- undergoes class switching to develop new classes of antibodies
- differentiates into plasma cells that are specialized to produce antibodies
Humoral immunity occurs in multiple phases including
- the primary response that occurs immediately after B-cell activation
- the secondary response after further differentiation of B-cells

Activation of Humoral-Mediated Immunity

Humoral immunity can be activated by two classes of antigens including
- thymus independent antigens that do not require T-cell help
- thymus dependent antigens that require T-cell help

Activation of Humoral Mediated Immunity
Feature	Thymus Independent	Thymus Dependent
Function	Detect conserved non-peptide antigens Identify pathogens that are missed by T-cells	Detect peptide antigens Cooperate with T-cells to clear pathogens
Activation steps	Crosslinking of B-cell receptors by polymeric antigens Examples include bacterial cell wall or lipopolysaccharide Activation by mitogens to promote general B-cell activity	Endocytosis of protein antigens that are detected by the B-cell receptor Processing of these antigens in endosomes and presentation on MHC class 2 Recognition of MHC complexes by activated helper T-cells Interaction of costimulatory CD40 on B-cells with CD40 ligand Differentiation after cytokine stimulation
Limitations	Does not lead to class switching or affinity maturation Does not produce immunological memory (require adjuvent)	Requires peptide antigen Must have functional helper T-cells

Affinity Maturation and Isotype Switching

After B-cells are activated they can undergo two main processes including
- affinity maturation to increase receptor affinity
- isotype switching to produce different antibody isotypes
Affinity maturation is a coordinated process with distinct stages including
- migration of B-cells to secondary lymphoid organs where
  - B-cells proliferate in germinal centers to form a colony
  - the B-cell receptor is randomly mutated in different cells
- selection of the cells with the highest affinity receptors within the colony by
  - providing a limited number of survival signals
  - allowing mutated B-cells to compete for these signals
  - pruning less effective B-cells through apoptosis
Isotype switching is stimulated after activation and
- occurs in germinal centers of secondary lymphoid organs
- is the process of irreversibly switching constant regions by DNA rearrangement with
  - removal of μ (IgM) and δ (IgD) type constant regions
  - addition of other constant regions making IgG, IgE, and IgA
- is controlled by stimulation with specific cytokines
  - no specific IL required for IgG production
  - IL-4 produces IgE
  - IL-5 produces IgA

Primary and Secondary Responses

Upon activation distinct populations of B-cells will develop including
- effector B-cells that mediate the primary response by
  - secreting antibodies
  - secreting cytokines
- proliferating B-cells that mediate the secondary response after
  - undergoing affinity maturation and class switching
  - differentiating into plasma cells
These responses differ in a variety of key aspects

Primary versus Secondary Responses
Feature	Primary Response	Secondary Response
Function	Immediately secrete antibodies Contain infection while secondary response develops	Develop into a more effective response with higher affinity Clear infection after development
Antibody type	Low affinity IgM	High affinity IgG IgA in mucosal infections IgE in parasitic infections
Timing	Early in infection	Late in infection

Blood, Plasma, Serum	Reference Range
ALT	8-20 U/L
Amylase, serum	25-125 U/L
AST	8-20 U/L
Bilirubin, serum (adult) Total // Direct	0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca²⁺)	8.4-10.2 mg/dL
Cholesterol, serum	Rec: < 200 mg/dL
Cortisol, serum	0800 h: 5-23 μg/dL //1600 h: 3-15 μg/dL 2000 h: ≤ 50% of 0800 h
Creatine kinase, serum	Male: 25-90 U/L Female: 10-70 U/L
Creatinine, serum	0.6-1.2 mg/dL
Electrolytes, serum
Sodium (Na⁺)	136-145 mEq/L
Chloride (Cl^-)	95-105 mEq/L
Potassium (K⁺)	3.5-5.0 mEq/L
Bicarbonate (HCO₃^-)	22-28 mEq/L
Magnesium (Mg²⁺)	1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)
24-28 wks // 32-36 wks	30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks	40-220 ng/mL // 80-350 ng/mL
Ferritin, serum	Male: 15-200 ng/mL Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma	Male: 4-25 mIU/mL Female: premenopause: 4-30 mIU/mL midcycle peak: 10-90 mIU/mL postmenopause: 40-250
pH	7.35-7.45
PCO₂	33-45 mmHg
PO₂	75-105 mmHg
Glucose, serum	Fasting: 70-110 mg/dL 2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation	Fasting: <5 ng/mL Provocative stimuli: > 7ng/mL
Immunoglobulins, serum
IgA	76-390 mg/dL
IgE	0-380 IU/mL
IgG	650-1500 mg/dL
IgM	40-345 mg/dL
Iron	50-170 μg/dL
Lactate dehydrogenase, serum	45-90 U/L
Luteinizing hormone, serum/plasma	Male: 6-23 mIU/mL Female: follicular phase: 5-30 mIU/mL midcycle: 75-150 mIU/mL postmenopause 30-200 mIU/mL
Osmolality, serum	275-295 mOsmol/kd H₂O
Parathyroid hormone, serume, N-terminal	230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C)	20-70 U/L
Phosphorus (inorganic), serum	3.0-4.5 mg/dL
Prolactin, serum (hPRL)	< 20 ng/mL
Proteins, serum

Hematologic	Reference Range
Bleeding time	2-7 minutes
Erythrocyte count	Male: 4.3-5.9 million/mm³ Female: 3.5-5.5 million mm³
Erythrocyte sedimentation rate (Westergren)	Male: 0-15 mm/h Female: 0-20 mm/h
Hematocrit	Male: 41%-53% Female: 36%-46%
Hemoglobin A1c	≤ 6 %
Hemoglobin, blood	Male: 13.5-17.5 g/dL Female: 12.0-16.0 g/dL
Hemoglobin, plasma	1-4 mg/dL
Leukocyte count and differential
Leukocyte count	4,500-11,000/mm³
Segmented neutrophils	54%-62%
Bands	3%-5%
Eosinophils	1%-3%
Basophils	0%-0.75%
Lymphocytes	25%-33%
Monocytes	3%-7%
Mean corpuscular hemoglobin	25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration	31%-36% Hb/cell
Mean corpuscular volume	80-100 μm³
Partial thromboplastin time (activated)	25-40 seconds
Platelet count	150,000-400,000/mm³
Prothrombin time	11-15 seconds
Reticulocyte count	0.5%-1.5% of red cells
Thrombin time	< 2 seconds deviation from control
Volume
Plasma	Male: 25-43 mL/kg Female: 28-45 mL/kg
Red cell	Male: 20-36 mL/kg Female: 19-31 mL/kg

Cerebrospinal Fluid	Reference Range
Cell count	0-5/mm³
Chloride	118-132 mEq/L
Gamma globulin	3%-12% total proteins
Glucose	40-70 mg/dL
Pressure	70-180 mm H₂O
Proteins, total	< 40 mg/dL

Sweat	Reference Range
Chloride	0-35 mmol/L
Urine
Calcium	100-300 mg/24 h
Chloride	Varies with intake
Creatinine clearance	Male: 97-137 mL/min Female: 88-128 mL/min
Estriol, total (in pregnancy)
30 wks	6-18 mg/24 h
35 wks	9-28 mg/24 h
40 wks	13-42 mg/24 h
17-Hydroxycorticosteroids	Male: 3.0-10.0 mg/24 h Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total	Male: 8-20 mg/24 h Female: 6-15 mg/24 h
Osmolality	50-1400 mOsmol/kg H₂O
Oxalate	8-40 μg/mL
Potassium	Varies with diet
Proteins, total	< 150 mg/24 h
Sodium	Varies with diet
Uric acid	Varies with diet
Body Mass Index (BMI)	Adult: 19-25 kg/m²