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Active Transport and Factors Affecting Facilitated Diffusion

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PART 1: ACTIVE TRANSPORT

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A. Primary Active Transport

• Na⁺-K⁺ ATPase
• H⁺ ATPase
• H⁺-K⁺ ATPase
• Ca²⁺ ATPase

• A larger alpha (α) subunit (~100,000 molecular weight) - contains 3 Na⁺ binding sites on the intracellular side, 2 K⁺ binding sites on the extracellular side, and ATPase activity
• A smaller beta (β) subunit (~55,000 molecular weight) - anchors the complex in the lipid membrane

1. Three Na⁺ ions bind to the intracellular sites, and two K⁺ ions bind to the extracellular sites
2. ATPase is activated → cleaves one ATP molecule → releases high-energy phosphate
3. This energy causes a conformational change in the protein
4. 3 Na⁺ are extruded outward; 2 K⁺ are transported inward
5. Net result: low intracellular Na⁺, high intracellular K⁺, and a resting membrane potential of about -70 mV

• Maintains Na⁺/K⁺ concentration gradients across cell membranes
• Establishes the negative intracellular electrical potential
• Controls cell volume - prevents osmotic swelling and lysis
• Powers nerve signal transmission (60-70% of energy in nerve cells goes to this pump)

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B. Secondary Active Transport

1. Co-transport (Symport)

• High extracellular Na⁺ (maintained by the Na⁺-K⁺ pump) provides the driving force
• A carrier protein has two binding sites on the exterior: one for Na⁺, one for glucose
• When both bind simultaneously, a conformational change occurs transporting both into the cell
• This moves glucose against its concentration gradient using Na⁺'s downhill gradient
• This is critical in the intestinal epithelium and renal tubules for glucose absorption
• A similar mechanism exists for amino acid absorption (at least 5 types of amino acid co-transporters)

2. Counter-transport (Antiport)

• Na⁺ moves inward down its gradient; Ca²⁺ is simultaneously transported outward
• Critically regulates intracellular Ca²⁺ concentration in cardiac and smooth muscle cells

• Na⁺ moves in; H⁺ is extruded outward
• Important in acid-base regulation

Key distinction: In secondary active transport, energy comes indirectly from the Na⁺ gradient established by the primary Na⁺-K⁺ pump. The process is therefore still energy-dependent, just one step removed.

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PART 2: FACTORS AFFECTING FACILITATED DIFFUSION

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Factors That Affect the Rate of Facilitated Diffusion

• The rate of facilitated diffusion is proportional to the concentration difference (Co - Ci) between outside and inside the cell
• Net diffusion ∝ (Co - Ci)
• A larger gradient → faster net transport rate
• However, unlike simple diffusion, this relationship is not linear - it approaches a maximum (V_max) as the carrier becomes saturated

• Each carrier protein can only flip conformation at a finite rate
• When all carriers are occupied by substrate molecules, the maximum transport rate (V_max) is reached - this is called saturation or the transport maximum (Tm)
• Increasing the number of carrier proteins in the membrane increases V_max
• Example: Insulin stimulates the translocation of GLUT4 glucose transporters from intracellular vesicles to the plasma membrane, increasing membrane carrier density and raising V_max for glucose uptake in skeletal muscle, adipose tissue, and heart by 10- to 20-fold

• Each carrier is specific for a particular molecule or group of structurally similar molecules
• For example, GLUT transporters handle glucose, galactose, and fructose (structurally similar monosaccharides) but not other sugars
• Competitive inhibition can occur when two similar substances compete for the same carrier

• Higher temperature increases the kinetic (thermal) energy of molecules
• This increases both the rate of molecular collisions with the carrier and the speed of conformational changes in the carrier protein
• Within physiological range, increased temperature generally increases the rate of facilitated diffusion

• For charged particles, the electrochemical gradient (not just concentration) determines net movement
• An electrical potential difference can either enhance or oppose diffusion of ions through their carriers
• At the Nernst potential, electrical and concentration forces exactly balance, producing no net diffusion

• Increased hydrostatic pressure on one side of the membrane increases the force with which molecules strike the membrane
• This slightly increases the rate of diffusion (including facilitated diffusion) toward the low-pressure side

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Summary Table

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ANSWER 1: ERYTHROPOIESIS

Definition

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Regulation by Erythropoietin

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Stages of Erythropoiesis (Developmental Sequence)

Pluripotent Stem Cell
        ↓
CFU-GEMM (Colony-Forming Unit - Granulocyte, Erythroid, Monocyte, Megakaryocyte)
        ↓
BFU-E (Burst-Forming Unit - Erythroid)
        ↓
CFU-E (Colony-Forming Unit - Erythroid)
        ↓
Normoblast (Pronormoblast → Basophilic → Polychromatic → Orthochromatic)
        ↓
Reticulocyte (released into blood)
        ↓
Mature Erythrocyte

1. Pronormoblast (Rubriblast): Largest recognizable red cell precursor; large nucleus; basophilic cytoplasm due to abundant ribosomes for hemoglobin synthesis.
2. Basophilic Normoblast: Active hemoglobin synthesis begins; nucleus shrinks; cytoplasm intensely basophilic.
3. Polychromatic Normoblast: Mixed staining (basophilic + eosinophilic) as both RNA and hemoglobin are present.
4. Orthochromatic Normoblast (Acidophilic): Pyknotic (dense, condensed) nucleus; cytoplasm nearly full of hemoglobin. At this stage, the nucleus is extruded.
5. Reticulocyte: Anucleate; retains ribosomes and mRNA; still capable of synthesizing hemoglobin. Released from bone marrow, circulates for 1-2 days, and matures in the spleen where ribosomes and mRNA are lost. Reticulocyte count in normal blood: ~0.5-1.5%.
6. Mature Erythrocyte: Biconcave disc, ~7-8 µm; no nucleus or organelles; lifespan ~120 days; destroyed by macrophages in the spleen, liver, and bone marrow (reticuloendothelial system).

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Requirements for Erythropoiesis

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Clinical Significance

• Polycythemia: Excess EPO production (e.g., from renal cell carcinoma or high altitude) → excess RBC production
• Anemia of chronic kidney disease: Reduced EPO secretion → insufficient erythropoiesis (treated with recombinant EPO - erythropoiesis-stimulating agents)
• JAK/STAT signaling disruption is associated with myeloid/lymphoid leukemias and Fanconi anemia (bone marrow failure)

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ANSWER 2: ANEMIA

Definition

• Males: Hb < 13.5 g/dL
• Females: Hb < 12.0 g/dL
• Pregnant women: Hb < 11.0 g/dL

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Classification

A. By Red Cell Size (MCV-Based Morphological Classification)

• Iron deficiency anemia - most common globally; inability to make heme
• Thalassemia - defects in globin protein synthesis (α or β chains)
• Anemia of chronic disease/inflammation - cytokine-mediated inhibition of iron reutilization
• Sideroblastic anemia - defects of heme synthesis

• Oval macrocytes (megaloblastic): Vitamin B12 deficiency, Folate deficiency, medications (chemotherapy, antiseizure drugs), myelodysplasia
• Round macrocytes (non-megaloblastic): Alcohol use, liver disease, hypothyroidism, reticulocytosis, dysproteinemia

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B. By Mechanism (Pathophysiological Classification)

• Bone marrow failure (aplastic anemia)
• Nutritional deficiencies (iron, B12, folate)
• Chronic kidney disease (low EPO)
• Myelophthisic anemia (marrow replacement by tumor/fibrosis)

• Acquired: Autoimmune hemolytic anemia (warm or cold antibody), mechanical hemolysis (prosthetic valves), microangiopathic (TTP/HUS), infections (malaria)
• Congenital: Hemoglobinopathies (sickle cell disease - HbS polymerization causes vaso-occlusion and hemolysis), enzyme defects (G6PD deficiency), membrane defects (hereditary spherocytosis)

• Acute blood loss → normocytic then regenerative (elevated reticulocytes)
• Chronic blood loss → iron deficiency → microcytic anemia

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Key Diagnostic Indicator

• Elevated reticulocytes → hemolysis or blood loss (marrow responding)
• Low reticulocytes → inadequate production (marrow failure or nutritional deficiency)

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Clinical Features

• Fatigue, pallor, dyspnea on exertion, palpitations
• Severe anemia: high-output cardiac failure, angina
• Sickle cell disease note: Intravascular hemolysis increases unconjugated bilirubin → exceeds hepatic conjugation capacity → hyperbilirubinemia → pigmented (calcium bilirubinate) gallstones

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Treatment Principles

• Iron deficiency: Oral/IV iron supplementation
• B12 deficiency: Cyanocobalamin injection (IM, especially if pernicious anemia)
• Folate deficiency: Folic acid 5 mg/day
• Hemolytic anemia: Treat underlying cause; steroids for autoimmune types
• Severe/symptomatic: Blood transfusion

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ANSWER 3: IMMUNITY

Definition

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I. Innate Immunity (Natural / Non-specific)

Features:

Components:

• Skin (intact epithelium)
• Mucosal epithelia (respiratory, GI, urogenital tracts)
• Antimicrobial molecules (defensins, lysozyme in saliva/tears, gastric acid)
• Ciliary action in respiratory tract

• Phagocytes:
  • Neutrophils - first responders; engulf and kill bacteria via reactive oxygen species and lysosomal enzymes
  • Macrophages - tissue-resident phagocytes; present antigens to adaptive immune cells; produce cytokines
• Dendritic cells - bridge between innate and adaptive immunity; the most potent antigen-presenting cells (APCs)
• Natural Killer (NK) cells - destroy virally infected cells and tumor cells without prior sensitization; recognize absence of MHC class I ("missing self")
• Mast cells - release histamine and other mediators; important in allergy and parasite defense
• Innate Lymphoid Cells (ILCs) - include NK cells; diverse functions

• Complement system - cascade of proteins that opsonize bacteria, lyse pathogens (membrane attack complex), and recruit inflammatory cells
• Lectins (mannose-binding lectin - recognizes microbial surface sugars)
• Acute phase proteins (CRP, fibrinogen)
• Cytokines/Interferons (type I IFNs limit viral spread)

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II. Adaptive Immunity (Specific / Acquired)

Features:

Two Arms of Adaptive Immunity:

• B lymphocytes produce antigen-specific antibodies (immunoglobulins)
• Activated by antigen + T helper cell signals (CD4+ T cells)
• Differentiate into plasma cells (antibody factories) and memory B cells
• Antibody functions: neutralization, opsonization, complement activation, ADCC (antibody-dependent cell-mediated cytotoxicity)
• Immunoglobulin classes: IgM (primary response), IgG (secondary response, crosses placenta), IgA (mucosal), IgE (allergy/parasites), IgD (B cell activation)

• CD4+ T helper cells:
  • Recognize antigens on MHC class II molecules (on APCs)
  • Th1 cells: activate macrophages and CD8+ cells (intracellular pathogens)
  • Th2 cells: help B cells; direct response to extracellular parasites
  • Th17 cells: defense against fungi and extracellular bacteria
• CD8+ Cytotoxic T lymphocytes (CTLs):
  • Recognize antigens on MHC class I (on all nucleated cells)
  • Kill virally infected cells and tumor cells via perforin/granzymes and Fas-FasL pathway
• Regulatory T cells (Tregs): Suppress immune responses; prevent autoimmunity

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Interaction Between Innate and Adaptive Immunity

• Innate immunity activates adaptive responses - dendritic cells present antigens to T cells in lymph nodes
• Adaptive immunity enhances innate mechanisms (e.g., IgG opsonizes bacteria for phagocytosis)
• This cross-talk is fundamental to effective host defense

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ANSWER 4: BLOOD COAGULATION

Definition

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Events of Hemostasis (Overview)

1. Vascular constriction - immediate reflex
2. Platelet plug formation - primary hemostasis
3. Coagulation cascade - formation of fibrin clot (secondary hemostasis)
4. Fibrous tissue repair - permanent sealing

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Stage 1: Vascular Spasm

• Local myogenic spasm
• Autacoid factors from traumatized tissues
• Nervous reflexes (pain impulses from damaged area)
• Thromboxane A2 released by activated platelets

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Stage 2: Platelet Plug Formation (Primary Hemostasis)

• Minute discs, 1-4 µm in diameter
• Formed from megakaryocytes in bone marrow
• Normal count: 150,000-450,000/µL
• Half-life: 8-12 days
• Contain: actin/myosin, thrombostenin, prostaglandin-synthesizing enzymes, fibrin-stabilizing factor, ADP/ATP stores, platelet-derived growth factor (PDGF)

1. Adhesion: Exposed subendothelial collagen (after endothelial damage) activates platelets via glycoprotein surface receptors. von Willebrand Factor (vWF) acts as a bridge between collagen and platelet receptor GPIb.
2. Activation: Platelets become activated → release ADP, thromboxane A2, and serotonin from their granules (degranulation)
3. Aggregation: Released ADP causes nearby platelets to swell and aggregate → platelet plug seals small cuts and vascular holes

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Stage 3: Blood Coagulation (Coagulation Cascade)

Prothrombin activator → converts Prothrombin → Thrombin → converts Fibrinogen → Fibrin clot

A. Extrinsic Pathway (Tissue Factor Pathway)

1. Tissue Factor (Factor III / Thromboplastin) released from traumatized endothelial cells/tissues
2. Tissue factor + Factor VII + Ca²⁺ → activates Factor X (Xa)
3. Factor Xa + Factor Va + Ca²⁺ + phospholipids → Prothrombin activator (Prothrombinase complex)
4. Prothrombin activator + Ca²⁺ → Prothrombin (II) → Thrombin (IIa)

B. Intrinsic Pathway (Contact Activation Pathway)

1. Factor XII is activated by contact with exposed collagen or foreign surfaces → Factor XIIa
2. XIIa activates Factor XI → XIa
3. XIa + Ca²⁺ activates Factor IX → IXa
4. IXa + Factor VIIIa + Ca²⁺ + phospholipids → activates Factor X → Xa
5. Factor Xa + Va → Prothrombin activator → same final pathway as above

C. Common Pathway

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Role of the Liver and Vitamin K

• Prothrombin, fibrinogen, and most other clotting factors are synthesized in the liver
• Vitamin K is required for hepatic activation of Factors II, VII, IX, X (and Protein C, S)
• Liver disease or vitamin K deficiency → reduced clotting factor synthesis → bleeding tendency

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Positive Feedback of Clotting

• Acting proteolytically on Factors VIII, IX, X, XI, XII
• Converting more prothrombin to thrombin
• Stimulating platelet aggregation

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Prevention of Abnormal Clotting (Anticoagulation)

• Intact endothelium: Produces prostacyclin (PGI2) and nitric oxide - inhibit platelet aggregation; thrombomodulin activates Protein C
• Antithrombin III: Neutralizes thrombin and other proteases
• Heparin: Activates antithrombin III (used clinically)
• Protein C and S: Inactivate Factors Va and VIIIa
• Tissue Plasminogen Activator (t-PA): Activates plasmin → fibrinolysis (clot dissolution)

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ANSWER 5: BLOOD GROUPS

Introduction

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I. ABO Blood Group System

Antigens

• A common core glycan is produced in all individuals
• Most individuals express a fucosyltransferase that converts this to the H antigen
• A gene on chromosome 9 encodes a glycosyltransferase that further modifies H antigen:
  • A allele: enzyme adds N-acetylgalactosamine → forms A antigen
  • B allele: enzyme adds galactose → forms B antigen
  • O allele: gene product has no enzymatic activity → only H antigen expressed

• Blood type O: OO genotype (only H antigen)
• Blood type A: AA or AO genotype
• Blood type B: BB or BO genotype
• Blood type AB: AB genotype (both A and B antigens)
• Bombay phenotype: Rare mutation in fucosyltransferase → cannot make H antigen → no A, B, or H antigens; produces anti-H, anti-A, and anti-B antibodies

Antibodies (Agglutinins)

Transfusion Compatibility:

Transfusion Reaction (ABO Incompatibility)

1. Preexisting IgM antibodies bind donor RBCs
2. Complement activation → intravascular hemolysis
3. Hemoglobin released → acute renal tubular necrosis and kidney failure
4. Massive cytokine release (TNF, IL-1) → high fever, shock
5. Disseminated intravascular coagulation (DIC) → paradoxical bleeding (clotting factors consumed faster than synthesized)

ABO antigens are also expressed on endothelial cells, so ABO compatibility is essential not just for blood transfusion but also for organ transplantation (to prevent hyperacute rejection).

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II. Rh Blood Group System

Antigens

• Rh antigens are non-glycosylated, hydrophobic membrane proteins (unlike ABO carbohydrate antigens)
• Encoded by two tightly linked, highly homologous genes; the clinically relevant one is RhD
• Rh positive: Expresses RhD antigen (~85% of population)
• Rh negative: ~15% of population has deletion or alteration of the RhD allele

Antibodies

• Unlike ABO, Rh-negative individuals do NOT have pre-formed anti-Rh antibodies
• Anti-Rh antibodies are produced only after exposure to Rh-positive blood (sensitization)
• Being a protein antigen, it stimulates class-switched IgG antibodies (not IgM)
• Critical difference: IgG can cross the placenta; IgM cannot

Hemolytic Disease of the Fetus and Newborn (HDFN / Erythroblastosis Fetalis)

1. Rh-negative mother carries an Rh-positive fetus (if father is Rh-positive)
2. During first delivery, fetal RBCs enter maternal circulation → mother gets sensitized → produces anti-RhD IgG
3. In a subsequent Rh-positive pregnancy, maternal anti-RhD IgG crosses the placenta
4. Maternal IgG destroys fetal RBCs → severe fetal anemia → compensatory extramedullary hematopoiesis → erythroblasts in circulation → erythroblastosis fetalis
5. Consequences: hydrops fetalis, kernicterus (bilirubin brain damage), stillbirth

• Administer anti-RhD immunoglobulin (Rh immune globulin / RhoGAM) to the mother within 72 hours of delivery of first Rh-positive baby
• Mechanism: Passive antibodies clear fetal RhD-positive RBCs from maternal circulation before they can trigger an immune response (possibly via Fc receptor-mediated B cell inhibition)
• Also given at 28 weeks gestation as prophylaxis

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III. Other Blood Group Systems (Brief)

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Summary Table: ABO vs. Rh

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IMMUNITY: CELL-MEDIATED AND HUMORAL IMMUNITY

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PART 1: CELL-MEDIATED IMMUNITY (CMI)

Definition

Origin and Maturation of T Cells

• T cells originate from pluripotent stem cells in the bone marrow
• They migrate to the thymus for maturation and education
• In the thymus, T cells undergo:
  • Positive selection - T cells that can recognise self-MHC are kept
  • Negative selection (clonal deletion) - autoreactive T cells (those that react to self-antigens) are eliminated → this creates self-tolerance and prevents autoimmunity
• Mature T cells leave the thymus and circulate through blood and lymphoid tissues

Antigen Recognition - Role of MHC

• MHC Class I proteins (on all nucleated cells): present endogenous antigens (e.g., viral peptides, tumor antigens) → recognized by CD8+ T cells
• MHC Class II proteins (on APCs only): present exogenous antigens (e.g., extracellular bacteria) → recognized by CD4+ T cells

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Types of T Cells and Their Functions

1. T-Helper Cells (CD4+ / Th cells) - Most Numerous (~75% of T cells)

• IL-2 (Interleukin-2): amplifies the T-helper response (positive feedback); stimulates proliferation of cytotoxic T cells and regulatory T cells
• IFN-γ: activates macrophages to become more efficient killers
• Lymphokines stimulate B-cell growth and differentiation into plasma cells and antibodies
• Lymphokines slow macrophage migration (concentrating them at the site of infection)

HIV/AIDS destroys CD4+ T-helper cells, leaving the immune system almost completely paralyzed - this is why AIDS patients suffer from opportunistic infections.

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2. Cytotoxic T Cells (CD8+ / CTLs - Killer Cells)

• Recognize antigen presented on MHC Class I (on infected/tumor cells)
• Directly attack and kill target cells
• Killing mechanism:
  1. CTL binds tightly to the target cell via antigen-specific TCR
  2. Releases perforins - hole-forming proteins that punch channels in the target cell membrane
  3. Releases granzymes (serine proteases) that enter via perforin pores and activate apoptosis
  4. Also activates Fas-FasL pathway → programmed cell death (apoptosis)
  5. The CTL detaches and can kill multiple target cells sequentially
• Targets: Virally infected cells, tumor cells, transplanted foreign cells
• After killing, CTLs can persist in tissues for months

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3. Regulatory T Cells (CD4+ Tregs)

• Suppress the activity of cytotoxic T cells and T-helper cells
• Prevent autoimmunity and excessive tissue damage
• Maintain immune tolerance to self-antigens
• Secrete inhibitory cytokines (IL-10, TGF-β)
• Also generated by the thymus to suppress any autoreactive T cells that escape negative selection
• Clinical significance: Tregs may suppress anti-tumor immunity → research into downregulating Tregs in cancer immunotherapy (checkpoint inhibitors); upregulating Tregs in autoimmune diseases

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Memory T Cells

• Are preserved in lymphoid tissue throughout the body
• Respond far more rapidly and powerfully on subsequent exposure to the same antigen (secondary response)
• Can last for months to years

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Examples of Cell-Mediated Immunity in Action

• Defense against intracellular pathogens (Mycobacterium tuberculosis, Listeria, viruses)
• Killing of virus-infected cells (CTLs recognize viral peptides on MHC I)
• Rejection of organ transplants (CTLs attack foreign MHC molecules)
• Tumor surveillance (CTLs destroy cancer cells)
• Delayed-type hypersensitivity (Type IV) - e.g., tuberculin skin test, contact dermatitis

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PART 2: HUMORAL IMMUNITY

Definition

Origin and Maturation of B Cells

• B cells originate and mature in the bone marrow (where they undergo negative selection to eliminate autoreactive B cells)
• Mature naive B cells express surface IgM and IgD as B cell receptors (BCR)
• They circulate and home to the B cell zones (follicles) of secondary lymphoid organs (lymph nodes, spleen)

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Antigen Recognition by B Cells

• Membrane immunoglobulin (binds antigen)
• Igα and Igβ signaling proteins (transmit activation signal into the cell)

• Afferent lymphatics (small soluble antigens via conduits)
• Subcapsular sinus macrophages (large antigens)
• Follicular dendritic cells (FDCs) - display antigen for prolonged periods (days to weeks) to sustain B cell activation

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B Cell Activation

T-Dependent Responses (Protein Antigens - Most Common)

1. Antigen binds BCR → B cell internalizes and processes antigen → presents peptide fragments on MHC Class II to a CD4+ Th cell
2. CD40L (on T cell) binds CD40 (on B cell) - this costimulatory signal is essential for full B cell activation
3. T helper cytokines (IL-2, IL-4, IL-5, IL-6, IL-21) drive B cell proliferation and differentiation

• Activated B cells move into follicles → form germinal centers
• In germinal centers, two critical processes occur:
  • Affinity maturation: Somatic hypermutation of immunoglobulin genes → B cells with higher-affinity receptors are selected (by FDC-displayed antigen) → progressively higher-affinity antibodies are produced as the response matures
  • Heavy chain isotype (class) switching: Initial IgM response switches to IgG, IgA, or IgE depending on the cytokine environment (e.g., IL-4 → IgE; TGF-β → IgA)

1. B cells differentiate into:
   • Plasma cells - antibody-secreting factories; a single B cell generates up to 5000 plasma cells, each secreting ~2000 antibody molecules per second
   • Memory B cells - long-lived cells that mediate rapid secondary responses

T-Independent Responses (Polysaccharide/Lipopolysaccharide Antigens)

• Some antigens (e.g., bacterial polysaccharides) can activate B cells without T-helper cell help
• Produce mainly IgM antibodies (no class switching)
• Little affinity maturation or memory generated
• Important in defense against encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae)

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Antibodies (Immunoglobulins) - Structure and Classes

• Variable region (Fab): Binds antigen (unique for each antibody specificity)
• Constant region (Fc): Determines antibody class and effector function (complement activation, Fc receptor binding)

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Mechanisms by Which Antibodies Eliminate Pathogens

1. Neutralization: Antibodies bind to toxins or viral surface proteins → block their ability to bind host cells (e.g., anti-tetanus toxin IgG)
2. Opsonization: IgG coats bacteria → phagocytes (macrophages, neutrophils) recognize Fc region → enhanced phagocytosis
3. Complement Activation: IgM and IgG activate the classical complement pathway → MAC (membrane attack complex) lyses bacteria; C3b opsonizes; C5a recruits neutrophils
4. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): NK cells and macrophages bind Fc portion of IgG on target cells → kill the target cell
5. Agglutination / Precipitation: IgM agglutinates bacteria (clumps them) → easier phagocytosis

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Primary vs. Secondary Antibody Response

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Comparison: Cell-Mediated vs. Humoral Immunity