Immunology & Autoimmune Disorders and Antibodies😍

Innate vs Adaptive Immunity

• Gamma delta T lymphocytes:
• They are a subset of T cells that have innate-like properties.

Immune Privilege

• Organs like eye, brain, testes (seminiferous tubules), placenta limit immune responses
• prevent inflammatory damage.

• Allograft rejection is less likely in these areas.

Passive vs Active Immunity

Natural Killer (NK) Cells

Arms:

• Kill via antibody-dependent cell-mediated cytotoxicity (ADCC)
→ CD16 binds Fc region of IgG

Inhibitory arm:

• Prevents killing self-cells.
• Self-Cell Recognition (ID Card):
• Self-cells have MHC1 (ID card).
• NK sees MHC1 → Inhibitory arm activated → No kill.

Activating arm:

• Activating arm, NKG2D, then kills these cells.
• Requires Interleukin IL-2, IL-12, IL-15.

• Activated by:
• Nonspecific activation signal on target
• Lack of MHC I on target surface

• Viruses/cancers destroy MHC1.

• Mnemonic: Natural killer going 2 destroy (NKG2D)

CD Markers:

• CD16, CD56, CD94.
• Mnemonic: "16in bicep 56in chest and 94 kg weight" (describes "strong bahubali natural killer cell").

T Lymphocytes

T-cell Receptors (TCR):

• 95%: 
• Alpha-beta T lymphocytes.
• MHC dependent receptors for peptide antigens.

• 5%: 
• Gamma delta T lymphocytes → found in GIT, GUT
• They are a subset of T cells that have innate immunity like properties.
• Mucosa of GIT = Prevent Ag entry like innate immune cells
• Possess gamma delta (γδ) T cell receptors.
• directly recognize lipid antigens
• independently of MHC presentation.
• Direct killing of infected macrophages
• Provide protection against mycobacteria
• Kills extracellular bacteria by perforin granulysin pathway

CD Markers:

• Mnemonic: "CD markers = 1→8, 28"

Pan T-cell marker & signal transducing: 

• CD3 (on all T-cells)

• Mnemonic: Pantie size 3

Helper T-cell

• CD4.

• Help B cells make antibodies

• Secrete cytokines to recruit phagocytes & activate leukocytes

• ↓ → HIV 

• ↑ → Sarcoidosis.

• Mnemonic: For (CD4) helping (Helper)
• More help for SARATHA (↑ ratio)
• No help for HIV people (↓ ratio)

Types

• Mnemonic:
• 17 → 1 → 2
• 17 → 1 → 17
• 1 → 2 → 2, γ
• 2 → 3 → 13, 4, 5

• TH17:
• Releases IL-17.
• Mnemonic: 17 year old girl dont do anything

• TH1:
• IL-2
• Interferon-gamma
• granuloma formation.
• Mnemonic: Granny (Gamma granuloma) 2 (IL2) nu poyonnu Nokkan (NK cells)

• TH2:
• IL-4
• IL-5
• IL-13
• Mnemonic: 2nd helper→ Switch (switching) idumbo → Easy (Eosinophilic) ayi → Mucus (Mucus) drain cheyyum

Cytotoxic T-cell: 

• King → CD8

• CD8.

• Kill virus-infected & tumor cells

• Mechanisms:
• Apoptosis via CD95 → Extrinsic Pathway
• Perforin-Granzyme pathway.
• Express CD8, which binds MHC I on infected cells.

• Mnemonic: King is 95 year old → likes perforating grannies

CD4/CD8 Ratio:

• Normal: 2:1

• Rule of 8:
• MHC1 presents to CD8 (1x8=8, as "8 1's are 8").
• MHC2 presents to CD4 (2x4=8, as "four 2's are 8").

B Lymphocytes

B-cell Receptors:

• "Blessed with an MD degree":

• Have IgM, IgD (antibodies) as receptors from childhood.

Humoral Immunity

• Recognize & present antigen

• Undergo somatic hypermutation → improved antigen specificity

• Differentiate into plasma cells → secrete antibodies (immunoglobulins)

• Form memory B cells → faster secondary immune response

CD Markers:

• Mnemonic: "10 → 20 → 40 → 80s double double".

• Methodology for ANA

Antibody-dependent cellular cytotoxicity (ADCC)

Types of Immunoglobulins (Ig)

General Features

• Proteins produced by plasma cells.

• Detectable > 7 days after symptoms.

• All antibodies are made of:
• 2 Heavy chains (~50,000 Da)
• 2 Light chains (~25,000 Da)
• Chains are connected by disulfide bonds

• Chains contain:
• In light chains → 1 Variable + 1 Constant region
• In heavy chains → 1 Variable + 3 or 4 Constant regions

• Fab region:
• Antigen binding site
• Antigen binds to
• hypervariable region /
  CDR (Complementarity Determining Region)

• Fc region:
• Mediates biological activity (e.g., complement fixation)

Structure of Antibody

• Constant

• Carboxy terminal

• Complement binding

• Carbohydrate side chains

• Confers isotype (IgG, IgA, etc.)

Order of concentration in blood: GAMDE

• IgG > IgA > IgM > IgD > IgE

Comparison Table

• IgG crosses placenta → "G = Goes to baby"

• IgM = Massive + first Made, 5 units and 10 binding site

• IgA = Airway & secretions, A2 → 2 units

• IgE = Eosinophils, allergy, parasites

Antibody Diversity (Antigen Independent)

1. V(D)J Recombination:
• Light chain = VJ
• Heavy chain = V(D)J
• Mediated by RAG1/2

2. N-nucleotide addition by TdT

3. Heavy + Light chain pairing

Affinity Development/maturation

• Progressive increase in affinity of antibodies for antigen during immune response.

• Achieved by affinity maturation in germinal centers.

• Key steps:
• Somatic hypermutation → generates variants of BCR/antibody.
• Selection → high-affinity B cells survive, low-affinity die.
• via follicular dendritic cells + Tfh cells).

• Result:
• Secondary immune response produces high-affinity antibodies.
• Improves effectiveness of humoral immunity.

Somatic Hypermutation (SHM)

• Molecular mechanism underlying affinity maturation.

• Occurs in variable (V) region of Ig genes (esp. CDRs).

• Mediated by Activation-Induced Cytidine Deaminase (AID).

• Introduces point mutations → generates B cell clones with variable affinities.

• Selection favors B cells with improved antigen binding → survive & proliferate.

B-cell and T-cell Interaction (Isotype Switching)

• Two signals are required for
1. T-cell activation
2. B-cell activation
3. Class switching

• B cell picks up antigen → become Activated B cell → presents to T cell → B cell's CD40 receptor interact with CD40 ligand on T cell → T cell then releases IL-4

• Isotype Switching:
• Promotion of B cell from MD to GAMDE
• Requires IL4 (from T cell) and CD40
• IL-4 → B cell change from MD (IgM, IgD) to G, A, M, D, E.

• Mnemonic: "Char chalice" (IL-4 & CD40 ligand) are needed for the "change" or "switching".

Anergy

• A state where a T or B cell fails to respond to an antigen due to lack of costimulatory signal (Signal 2).

• Key in self-tolerance.

T-cell Activation

1. Antigen uptake by APC → migrates to lymph node.

2. Signal 1:
• Exogenous antigen → presented on MHC II → recognized by TCR on Th (CD4+) cell.
• Endogenous/cross-presented antigen → presented on MHC I → recognized by TCR on Tc (CD8+) cell.

3. Signal 2:
• B7 (CD80/86) on APC binds CD28 on naïve T cell → proliferation and survival.

4. Activated Th cell secretes cytokines.
• Tc cells → kill virus-infected cells.

Antigen Presenting Cells (APCs)

• Role: First cells to pick up antigen.

• Types:
• Professional APCs:
• Primary job is antigen presentation.
• Mnemonic: DBMci
• D: Dendritic cells.
• B: B cells.
• M: Macrophages.
• Non-professional APCs:
• Part-time antigen presentation.
• Epithelial cells
• Endothelial cells
• Fibroblasts.

• Mechanism:
• Present antigens on a "tray"/"plate"
• called Major Histocompatibility Complex (MHC).

Major Histocompatibility Complex (MHC)

• Control: By HLA gene on chromosome 6p.

HLA Gene Parts:

• MHC say HLo (HLA) to Antigen

Differences between MHC1 and MHC2:

• Mnemonic: All can present to King, but only spcl peple can present to manthri

Autoimmune Disorders and Antibodies

 

Disorder	Key Antibodies / Features	Mnemonic
Scleroderma	ㅤ	ㅤ
- Limited Scleroderma	Anti-centromere antibody.	"Limited to a place," so "centered to a place"
- Diffuse Scleroderma	Anti-topoisomerase antibody  (also Anti-SCL70).	"Diffuse" → "Topo (total body) isomease"
SLE (Systemic Lupus Erythematosus)	Most sensitive:  - Anti-nuclear antibody (ANA). Most specific:  - Anti-Smith (Anti-Sm) antibody. Both sens. & spec.: - Anti-dsDNA antibody. - Mnemonic: double benifit → DNA Neonates (rona):  - Anti-Ro antibody. Psychosis: - Anti-ribosomal P antibodies.	ㅤ
Drug-induced Lupus	Caused by SHIP drugs  (Sulfonamides, Hydralazine, Isoniazid, Procainamide, Dapsone). Anti-histone antibodies.	He throw stone (anti histone) if ur drug give him SLE
Sjögren's Syndrome	Dry eyes, dry mouth. Anti-SSA (Anti-Ro),  Anti-SSB (Anti-La).	Anti-SSA (Ro) "rona is sensitive"; Anti-SSB (La) "LA is specific"

ANA Immunofluorescence Patterns:

• Mnemonic: HAPPENS

Pattern	Target Antigen	Description / Notes
Centromere	Anti-centromere antibody	• Stains centromeres (discrete dots). • Seen in Limited Scleroderma (CREST)
Speckled	Anti-Sm, Anti-Ro (SSA), Anti-La (SSB)	• Most common; non-specific. • Seen in SLE, Sjögren’s, Scleroderma
Nucleolar	RNA / Nucleolar RNA	• Nucleolus stained (1–2 dots); • seen in Systemic Sclerosis
Peripheral (Rim)	dsDNA	• Periphery of nucleus dark; • classic for SLE
Homogeneous	Chromatin / Histone / nuclear	• Entire nucleus stained uniformly • Drug induced lupus

Spleen

Location & Protection

• Protected by 9th–11th ribs

Function

• Filters blood, stores WBCs and platelets

• Immune surveillance and response to blood-borne antigens

Histology Overview

Circulation Types

• Open circulation: Blood passes through cords into sinusoids

• Closed circulation: Blood directly enters sinusoids

Splenic Dysfunction (e.g., post-splenectomy, sickle cell autosplenectomy)

• ↓ IgM → ↓ complement activation → ↓ C3b opsonization

• ↑ susceptibility to encapsulated organisms

Post-splenectomy Findings

• Howell-Jolly bodies (nuclear remnants)

• Target cells

• ↑↑ Platelets (↓ sequestration/removal)

• ↑↑ WBCs (↓ sequestration)

Vaccination Advice

• Vaccinate against encapsulated organisms:
• Pneumococcus
• Haemophilus influenzae type B
• Neisseria meningitidis

Thymus

Thymus

 

 

• Site: Anterosuperior mediastinum

• Epithelium: Derived from 3rd pharyngeal pouch (endoderm)

• Lymphocytes: Derived from mesoderm

• T cells mature in Thymus

• B cells mature in Bone marrow, Spleen

Clinical Correlations

• Absent thymic shadow or hypoplastic thymus:
• Seen in SCID, DiGeorge syndrome

• Thymoma:
• Most common anterior mediastinal tumour
• Tumor of thymus
• Associated with:
• Myasthenia gravis
• Superior vena cava syndrome
• Pure red cell aplasia
• Good syndrome

General Features

• Capsulated

• "Sail-shaped" appearance on neonatal chest X-ray (CXR)

• Involutes by age 3 years

• Divided into lobules
• Each lobule has:
• Cortex:
• Darkly stained (many small lymphocytes)
• Immature T cells
• Medulla:
• Lightly stained (pale reticular cells + few lymphocytes)
• Mature T cells

• No lymphatic nodules

Lobular Structure

• Incomplete septa:
• Divide cortex, but not medulla
• Multiple cortices share common medulla

Unique Feature

• Hassalls (Thymic) corpuscles in medulla:



• Central hyaline mass
• Surrounded by concentric layers of dying reticuloepithelial cells

Differentiation of T Cells

Origin and Selection

• T-cell precursor originates in bone marrow.

• Migrates to thymus for maturation and selection.

✅ Positive Selection

• Occurs in thymic cortex.

• Selects T cells that can recognize self-MHC molecules (either class I or II).

• Only those cells get a survival signal.

❌ Negative Selection

• Eliminates T cells that bind too strongly to self-antigens.

• Occurs in thymic medulla.

Autoimmune Polyendocrine Syndrome Type 1:

• Negative selection absent
• Controlled by AIRE gene

• Drives expression of self-antigens in the thymus.

• AIRE deficiency →
• Chronic mucocutaneous candidiasis
• Hypoparathyroidism
• Adrenal insufficiency
• Recurrent Candida infections
→ Mnemonic: “Organs in air are affected → adrenal, parathyroid + candida in air will come”

IPEX Syndrome

• T Regulatory cell defect

• X linked

• Cause: FOXP3 deficiency → autoimmunity
• Immune dysregulation
• Polyendocrinopathy
• Enteropathy

• Other Symptoms:
• nail dystrophy, dermatitis

• Seen in male infants, often associated with diabetes.

Chronic Mucocutaneous Candidiasis

• Defect:
• T-cell dysfunction.
• Impaired cell-mediated immunity caused by Candida sp.
• Classic form in AIRE.

• Presentation:
• Persistent noninvasive Candida albicans infections of skin & mucous membranes.

• Findings:
• Absent in vitro T-cell proliferation in response to Candida antigens.
• Absent cutaneous reaction to Candida antigens.

IL-12 Receptor Deficiency

• Defect:
• ↓ Th1 response.
• Autosomal recessive.

• Presentation:
• Disseminated mycobacterial & fungal infections.
• May present after BCG vaccination.

• Findings:
• ↓ IFN-γ.
• Most common cause of Mendelian susceptibility to mycobacterial diseases (MSMD).