clinical immunology

innate immune response

The response consists of two phases (Figure 1.6). First is recognition that a

pathogen is present. This involves soluble proteins and cell-surface receptors

that bind either to the pathogen or to human cells and plasma proteins that

have been altered by the pathogen's presence. Once the pathogen has been

recognized, the second phase of the response recruits effector mechanisms

that kill or expel the pathogen. Mediating the effector mechanisms are effector

cells that engulf bacteria, kill virus-infected cells, and attack protozoa.

Supporting the effector cells is complement, a system of plasma proteins

that assists the effector cells by tagging pathogens with molecular flags.

Complement proteins can also kill pathogens without assistance from effector

cells by perturbing the integrity of the pathogens' membranes. Collectively,

these defenses comprise.

• The body's immediate, nonspecific defense against pathogens.

• Present from birth; cells include neutrophils, macrophages, NK cells, etc.

• Rapid response within hours

• Fixed

• Limited number of specificities

• Constant during the course of response

antigen

• A substance that can be specifically recognized by immune receptors, especially B-cell receptors, antibodies, or T-cell receptors

• Can be from microbes, toxins, proteins, etc.

Adaptive immunity

• Slow response in days to weeks

• Variable

• Numerous highly selective specificities

• Improves during the course of response

• Antigen-specific immune defense that develops after exposure

Innate Immunity vs Adaptive Immunity

The receptors of innate immunity are structurally of many different types. Each receptor recognizes molecular features that are common to groups of pathogens, and none isspecific for a particular pathogen. Conversely, the lymphocytes of adaptive immunity recognize pathogens using only one type of cell-surface receptor, but this receptor is made in billions of different versions.

Main Advantages of Adaptive Immunity

1. High specificity

   • Can distinguish between many different antigens.

2. Huge recognition diversity

   • The adaptive immune system can recognize an enormous variety of different antigens.

3. Immunological memory

   • After the first exposure, memory cells remain.

   • A second exposure can produce a faster and stronger response.

4. Improved response with repeated exposure

   • Adaptive responses can become more effective after repeated encounters with the same antigen.

Mast cell

Expulsion of parasites from the body by release of granules

containing histamine and other active agents

CD markers that can be used to identify T lymphocytes

CD3

Helper T → CD4

Cytotoxic T → CD8

CD markers that can be used to identify B lymphocytes

CD19, CD20

List the mature immune cell types that can arise from the common lymphoid precursor

• B lymphocytes

• T lymphocytes

• NK cells

Lymphoid → B, T, NK

List the mature immune cell types that can arise from the common myeloid precursor

• granulocytes, (which comprise neutrophils, eosinophils, and basophils)

• Dendritic cells

• Megakaryocytes → platelets

• Erythrocytes (red blood cells)

• Monocytes → macrophages

Myeloid → monocytes/macrophages + granulocytes

granulocytes (polymorphonuclear leukocytes)

Comprises neutrophils, eosinophils, and basophils. These effector cells all have cytoplasmic granules fill which is why they are granulocytes.

Neutrophils

• polymorphonuclear (usually 2-5 lobes) granulocyte with tiny pink/blue cytoplasmic granules

• Important in acute inflammation and bacterial defense

lymphocytes

mononuclear cells with round nucleus, high nucleus to cytoplasmic ratio (big nucleus, very little cytoplasm around it) rare cytoplasmic granules. B cells t cells, and NK cells are all in this group because they cannot be distinguished morphologically using a microscope.

eosinophils

• usually, bilobed nucleus (like basophils) with large orange pink (salmon) colored cytoplasmic granules

• Important in parasite defense and allergic responses

basophils

• rare cells; usually bio\lobed nuclesus (like eosinophils) obscured by large purple purple black cytoplasmic granules.

• Important in inflammatory/allergic responses

Explain the relationship between monocytes and macrophages

Monocyte

• Found primarily in peripheral blood

• Circulating leukocyte

• Can leave the bloodstream and enter tissues

Macrophage

• A differentiated tissue phagocyte

• Develops from monocytes that migrate into tissues

• Engulfs pathogens, dead cells, and debris

• Can present antigen to T cells

Easy sequence:

• Bone marrow → monocyte → blood → tissue → macrophage

List the 2 tissues/organs that represent the primary lymphoid tissues

1. Bone marrow

• Site of blood-cell production

• B-cell development/maturation

2. Thymus

• Site of T-cell maturation

Memory trick:

• B = Bone marrow

• T = Thymus

Describe how a naïve lymphocyte enters a lymph node, and how it would exit if it did not

get stimulated by antigen

enter via arterioles (blood vessel), exit via efferent lymph

Describe how antigen enters a lymph node

anitgens enters lymph node via fluid drainijng from tissues (in afferent lymph vassals)

List where T lymphocytes and B lymphocytes are primarily located in the lymph nodes

and the white pulp of the spleen.

Lymph node

B cell zone → Outer (follicles)

T cell zone→ Middle

Spleen

B → follicles

T → PALS (periarteriolar lymphoid sheath)

CD antigen/marker

• A cell-surface molecule identified by a "CD" (cluster of differentiation) number

• Used to identify/classify immune cells

Primary lymphoid tissue

• Where lymphocytes develop and mature

• Bone marrow and thymus

Secondary lymphoid tissue

• Where mature lymphocytes encounter antigen and become activated

• Lymph nodes, spleen, MALT, etc.

Lymph

• Fluid collected from tissues that travels through lymphatic vessels

• Eventually e-mph nodes and returns to blood

PALS

• Periarteriolar lymphoid sheath

• t-cell region of the spleen's white pulp

GALT

• Gut-associated lymphoid tissue

• Lymphoid tissue associated with the gastrointestinal tract

BALT

Bronchus-associated lymphoid tissue

Lymphoid tissue associated with the respiratory tract

MALT

• Mucosa-associated lymphoid tissue

• Lymphoid tissue associated with mucosal surfaces

M cell

• Specialized epithelial cell that transports material from the lumen to underlying immune cells

• Important in mucosal immune surveillance, especially GALT

Describe how plasma proteins limit the spread of infection throughout the body

Plasma contains several proteins that help prevent an infection from spreading.

Major mechanisms:

1. Complement proteins

• Bind to microbes.

• Can directly damage microbial membranes.

• Help mark microbes for destruction (opsonization).

• Promote inflammation and recruitment of immune cells.

2. Pentraxins

• Bind to structures on microbes.

• Help identify microbes for phagocytosis.

• Can activate complement.

3. Acute-phase proteins

• Produced mainly by the liver in response to inflammatory cytokines.

• Circulate throughout the body.

• Help recognize and contain pathogens

phagocytosis

cellular process where cells engulf and digest large particles, such as pathogens and cellular debris, playing a crucial role in the immune response and maintaining tissue homeostasis

Describe how pentraxins and defensins function in innate immune system protection of

the body

Pentraxins

• Circulating proteins that bind to pathogens and effector molecules

• target for destruction

• Similar role to antibodies of the adaptive immune response

• Form a bridge between pathogen and phagocytes.

• Promote phagocytosis.

• Pentraxins = "tag the pathogen”

Defensins

• Defensins are antimicrobial peptides.

• Insert into microbial membranes.

• Disrupt membrane integrity.

• Kill microbes.

• Defensins = "damage the pathogan”

Identify the major macrophage cytokine that triggers the “acute phase” response and the proteins that are produced as a part of the acute phase response.

A major macrophage cytokine that triggers the acute-phase response is:

• IL-6

Macrophages release IL-6, which acts primarily on the liver.

• The liver then produces acute-phase proteins.

Important examples:

• C-reactive protein (CRP)

• Serum amyloid A (SAA)

• Fibrinogen

• Surfactant proteins

Pathway to memorize:

• Macrophage → IL-6 → liver → acute-phase proteins

• The acute-phase response is a systemic response to local infection/inflammation.

Describe the main functions of the inflammatory response

Earliest and most notable immune response:

• Signs: redness, swelling, heat, pain, loss of function.

Inflammatory response:

• Recruitment of leukocytes to the site of infection via soluble and cellular receptors

• Reduced integrity of blood vessels allows for leukocytes to enter infected tissues

Macrophage activation

• Release of cytokines (pro/inflammatory)

Helps induce adaptive immune response if necessary.

THINK: Inflammation gets immune cells and immune proteins from the blood to the site where they're needed.

Identify the cytokines and chemokines released by macrophages that cause beneficial

LOCAL immune system effects and the specific effects that each of the cytokines is

responsible for.

at the site of infection, activated resident macrophages secrete inflammatory cytokines.

• TNF-a (cytokine) induces blood vessels to be more permeable, enabling cells, fluid, and soluble effectors to enter infected tissue.

• IL-6 (cytokine) induces fat and muscle cells to metabolize, generate heat, and raise temperature in the infected tissue.

• IL-12 (cytokine) recruits and activates natural killer cells to secrete cytokines that strengthen macrophages’ response to infection

• CXCL8 (chemokine) recruits neutrophils from the blood and directs them to the infected tissue

• CCL2 (Chemokine) recruits monocytes from the blood and directs them to the infected tissue.

cytokines

Cytokines are small signaling proteins that allow cells to communicate with one another

• Cytokines that start the immune response are pro-inflammatory

• Cytokines that limit the immune response are anti-inflammatory

chemokines

attract effecter cells into infected tissues.

What are Pattern Recognition Receptors? Differentiate between PAMPs and DAMPs

PRRs are receptors used by innate immune cells to recognize common molecular patterns associated with infection or tissue damage.

• Receptors on all leukocytes, as well as some epithelial and endothelial cells.

PAMP = Pathogen-Associated Molecular Pattern

• These are any molecular structures associated with microbes recognized by PRR

• PAMP = Pathogen

DAMP = Damage-Associated Molecular Pattern

• These are molecules released or exposed by damaged or stressed cells/tissues. They signal that tissue injury has occurred. DAMP = Damage

Describe the process of leukocyte recruitment from blood vessels into surrounding

tissues

When tissue becomes infected or damaged, leukocytes must leave the bloodstream and enter the tissue.

The sequence:

1. Rolling

Leukocytes temporarily attach to endothelial cells using selectins.

⬇

2. Activation

Chemokines activate leukocytes.

⬇

3. Firm adhesion

Leukocyte integrins become activated and bind strongly to endothelial adhesion molecules.

⬇

4. Transmigration / diapedesis

The leukocyte moves between endothelial cells and leaves the blood vessel.

⬇

5. Chemotaxis

The leukocyte follows a chemical gradient toward the site of infection.

Memorize:

ROLL → ACTIVATE → ADHERE → TRANS­MIGRATE → CHEMOTAXIS

Or:

"Rolling → Activation → Adhesion → Exit → Follow the signal."

What are the three systemic inflammatory cytokines? What tissues do they act on, and

what kind of response is produced?

Systemic effects to know

Cytokine	Tissue/organ	Main response
TNF-α	Muscle + fat	Changes metabolism; promotes breakdown of energy stores → (decreased viral and bacterial infections)
IL-1	Hypothalamus	Increased body temperature → decreased viral and bacterial infections
IL-6	Liver	Acute-phase protein production → activates complement opsonization
TNF-α + IL-1	Bone marrow	Increased leukocyte production/release → phagocytosis

What are the mechanisms of systemic shock?

1. Widespread vasodilation (due to TNF-a)

• Blood vessels become more dilated.

2. Increased vascular permeability

• Fluid leaves blood vessels and enters tissues.

3. Decreased blood volume/pressure

• Less effective circulating blood volume remains in the vascular system.

4. Poor tissue perfusion

• Organs don't receive enough blood and oxygen.

This can result in:

• Systemic inflammatory shock

Simple chain:

Cytokines (TNF-a) → vasodilation + vascular leakage → low blood pressure → inadequate tissue perfusion → organ dysfunction

Differentiate autoinflammation from (allo) inflammation

Autoinflammation

• Inflammation caused by activation of the innate immune system (not adaptive immunity) in response to abnormal/damaged components of the person's own body.

• It does not primarily require recognition of a foreign antigen by adaptive immunity.

• AUTO = self

• not adaptive immunity

Alloinflammation

• Inflammation caused by recognition of genetically different cells/tissues from another individual of the same species.

• This is particularly important in situations such as:

  • Transplantation

  • Transfusion-related immune responses

• ALLO = another individual

• involves adaptive immunity and innate

Neutrophils vs. Macrophages

Both are phagocytes, but they behave very differently.

Feature	Neutrophils	Macrophages
Lifespan	Short — usually hours to a few days	Much longer — weeks to years depending on tissue
Location	Mostly blood until recruited to tissues	Primarily tissues
Main role	Rapid response to infection	Long-term defense, cleanup, regulation, repair
Phagocytosis	Very strong	Very strong
Repeated use	Generally die after intense activity	Can survive and continue functioning
Antigen presentation	Limited	Yes — can present antigen to T cells
Tissue repair	Limited	Important
Can produce cytokines	Yes	Yes

• Neutrophil = emergency responder

• Macrophage = long-term resident

• Neutrophils arrive quickly and kill microbes, but they have a relatively short lifespan.

• Macrophages can remain in tissues much longer and can phagocytose, secrete cytokines, present antigen, and help with tissue repair.

Differentiate M1 and M2 macrophages

M1 = Intracellular infections

M2 = wound healing, antiparasitic infections

List the different PRRs activated dendritic cells use to traffic molecules to the lymph nodes, and what cell(s) respond to each type of PRR activation

PRR activation tells dendritic cells that danger is present and promotes their migration to lymph nodes, where they can activate T cells.

Identify the main function of plasmacytoid dendritic cells.

The main function of plasmacytoid dendritic cells (pDCs) is:

Producing large amounts of Type I interferons

Especially:

IFN-α

IFN-β

They are particularly important in antiviral innate immunity.

Memorize:

pDC → Type I IFN → antiviral defense

Explain what is meant by “respiratory burst” regarding phagocytes

The respiratory burst is the rapid production of reactive oxygen species (ROS) by activated phagocytes.

It happens after a phagocyte has engulfed a pathogen.

Simplified process:

Phagocytosis

↓

NADPH oxidase activated

↓

O₂ → reactive oxygen species

↓

ROS help kill the pathogen

Important ROS include:

Superoxide

Hydrogen peroxide

Other reactive oxygen products

The respiratory burst is an important mechanism for killing phagocytosed microbes

Identify the immune system defect that causes Chronic Granulomatous Disease

CGD is caused by a defect in:

NADPH oxidase

Remember:

NADPH oxidase → respiratory burst

Therefore:

Defective NADPH oxidase → defective respiratory burst → impaired killing of certain phagocytosed microbes

This makes patients particularly susceptible to certain bacterial and fungal infections.

Exam connection:

CGD = NADPH oxidase defect = respiratory burst defect

phagocytosis, netosis, apoptosis, pyroptosis, and trogocytosis

Process	What happens?	Common cell types	Inflammation?

Phagocytosis

Cell engulfs and digests target

Neutrophils, macrophages, dendritic cells

Usually can promote inflammation depending on context

NETosis

Neutrophils release DNA/proteins that form NETs to trap microbes

Neutrophils

Yes, generally

Apoptosis

Programmed cell death; cell is removed in an orderly manner

Most nucleated cells

Usually no

Pyroptosis

Inflammatory programmed cell death with membrane disruption

Macrophages, monocytes, other innate cells

Yes

Trogocytosis

Cell takes small pieces of membrane/material from another cell

Immune cells, including phagocytes

Can contribute to immune activation depending on context

Identify the two main functions of NK cells

1. Kill infected or abnormal cells

NK cells can kill:

Virus-infected cells

Some tumor/abnormal cells

They release cytotoxic molecules that cause target-cell death.

2. Produce cytokines

Especially:

IFN-γ

IFN-γ activates macrophages and helps promote antimicrobial immune responses.

Memorize:

NK = Kill + IFN-γ

Compare the three known ILCs based on what type of immunity they are associated with

ILC	Immunity	Major cytokines	Main association
ILC1	Type 1	IFN-γ	Intracellular microbes
ILC2	Type 2	IL-4, IL-5, IL-13	Parasites/allergy
ILC3	Type 3	IL-17, IL-22	Extracellular bacteria/fungi

Discuss how interferons (Type I and Type II together) activate NK cells to

combat/counteract infections

Type I IFNs (IFN-α/β) are produced during viral infections and activate NK cells. NK cells then kill infected cells and produce Type II IFN (IFN-γ), which activates macrophages and increases their ability to kill intracellular microbes.

Easy pathway: Virus → IFN-α/β → NK cell → IFN-γ → Macrophage activation

Describe the interaction between macrophages and NK cells, including the cytokines and

interferons involved

Macrophage

↓ releases IL-12 + IL-18

NK cell

↓ produces IFN-γ

Macrophage

↓ becomes more activated

Better killing of intracellular microbes

Describe the process of immunological (NK-cell) synapse, and the responses to activating

and inhibitory signals.

The NK-cell synapse is the organized contact between an NK cell and its target cell.

NK cells receive both:

• Inhibitory signal

Healthy cells typically express MHC class I. NK-cell inhibitory receptors recognize MHC I. This tells the NK cell: "This is a normal self cell — don't kill it."

• Activating signal

Stress or infection can cause a cell to express molecules recognized by activating NK receptors. If activating signals outweigh inhibitory signals, the NK cell kills the target.

• The basic decision:

Inhibitory signals dominate → DON'T KILL

Activating signal dominates → KILL

Identify the general role of Pattern Recognition Receptors in innate immune responses

• Pattern recognition allows innate immune cells to detect nonself and altered self

Soluble and cellular receptors that detect the presence of infecting organisms and recruit leukocytes to the infected tissue. These receptors operate using pattern recognition, the mechanism of examining molecules to determine if the motif present belongs to the host or to an outside entity, and among host cells, to distinguish between healthy cells and altered unhealthy cells.

List and describe each of the TLR subfamilies: Type I, II, III, IV (not each individual TLR), including general type of ligands, microbe type recognized, cells on which they appear (immune or other), and cellular location of receptor.

Describe how TLR’s main cell location relates to their target antigen type

Location	What TLRs mainly detect
Plasma membrane	lipids, lipoproteins, cell-wall components, carbohydrates
Endosome	Microbial nucleic acids → viral RNA/DNA or intracellular bacterial infections.

Describe the function of MyD88, and which TLR’s utilize this protein

• MyD88 is an adaptor protein that brings two signaling proteins together.

• Most TLRs use MyD88 except TLR3

Identify which of the interferons (IFN-α, IFN-β, or IFN-γ) are “Type I interferons” and the type of microbial infection they combat (ie, Bacterial? Viral? Fungal? Parasitic?)

Interferon	Type	Major role
IFN-α	Type I	Antiviral
IFN-β	Type I	Antiviral
IFN-γ	Type II	Activates immune responses, especially macrophages

IFN-α and IFN-β = Type I interferons

Describe the function of NFκB, IRF3, and IRF7 transcription factors and their cytokine/interferon production in response to cell surface (plasma membrane) or endosomal TLR binding

NF-κB, IRF3, and IRF7

Transcription Factor	Main Function	Activated By / Pathway	Main Products	Main Result
NF-κB	Promotes inflammation	TLR signaling, especially through MyD88	TNF, IL-1, IL-6	Inflammatory response
IRF3	Promotes antiviral responses	TLR signaling and RIG-I/MAVS pathways	Mainly IFN-β	Antiviral response
IRF7	Promotes and amplifies Type I interferon production	Endosomal TLR signaling and interferon signaling	Mainly IFN-α	Antiviral response

Identify the outcome of RIG-1 binding and activation of MAVS receptors

RIG-I is a cytosolic pattern-recognition receptor.

• It detects viral RNA inside the cytoplasm.

• Leads to the synthesis and secretion of type 1 interferons

On what type of leukocyte are scavenger receptors found? What is the function of scavenger receptors, and what kinds of ligands do they bind to

• PRRs on tissue-resident macrophages

Scavenger receptors bind a broad range of molecules and help cells:

• Recognize material

• Internalize material

• Remove potentially harmful substances

• Participate in microbial recognition

Types of ligands

They can recognize:

• Microbial components

• Modified lipids

• Damaged cellular material

• Other altered molecules

Describe the importance of the cGAS-STING pathway in the innate immune response

cGAS–STING Pathway

Step	What happens
cGAS	Detects DNA in cytosol
STING	Activates signaling
IRF3	Turns on Type I interferons
Result	Antiviral immune response

Remember: cGAS = DNA sensor → STING → Type I IFN.

• memorize → produce type 1 interferons (a,b)

Detail the structure and function of the inflammasome

Part	Function

Sensor

Detects microbes, cell damage, or danger signals

ASC	Adaptor protein that connects the sensor to caspase-1

Caspase-1

Processes IL-1β and IL-18 into active cytokines

IL-1β

Promotes inflammation

IL-18

Helps activate immune responses

Pyroptosis

Inflammatory form of programmed cell death

Overall result

Strong inflammatory immune response

The inflammasome is a cytosolic multiprotein complex that detects danger and activates inflammatory responses.

Complement (C′)

A group of plasma and membrane proteins that help destroy pathogens, promote inflammation, and enhance phagocytosis.

Opsonin

A molecule that coats a pathogen and makes it easier for phagocytes to recognize and ingest it. C3b is an important complement opsonin.

Anaphylatoxin

Small complement fragments, mainly C3a and C5a, that promote inflammation and activate/recruit immune cells.

Chemoattractant

A substance that causes immune cells to move toward a site of infection or inflammation. C5a is an important example.

Complement fixation

Activation of complement after recognition of a target, resulting in complement proteins binding to/depositing on the target.

CR# (Complement Receptor)

Receptors on immune cells that recognize complement fragments attached to pathogens or immune complexes

Opsonization vs. Complement Fixation

Opsonization	Complement Fixation
Coats a pathogen to make it easier to phagocytose	Complement proteins become activated and deposited on a target
Important opsonin: C3b	Can lead to opsonization, inflammation, and MAC formation

Easy memory:
Opsonization = “tag it for eating.”

Complement Cascade

Complement works as a cascade:

One protein activates → many molecules of the next protein → even more molecules downstream.

Each activated enzyme can activate many molecules of the next component, producing amplification

Advantage of Complement vs. Antibody

Complement can rapidly amplify and coat a pathogen with C3b without requiring a large amount of antibody already attached to the pathogen.

This is especially important for the innate immune response

Four Main Functions of Complement

Function	What it does

Opsonization

C3b coats pathogens → promotes phagocytosis

Inflammation

C3a/C5a promote inflammatory responses

Chemotaxis

C5a attracts immune cells to infection

Cell lysis

MAC (C5b–9) can create pores and lyse target cells

Three Complement Pathways

Pathway	How it starts	First Recognition Component

Classical

Antibody bound to antigen

C1q

Lectin

Recognizes microbial sugars such as mannose

MBL

Alternative

Spontaneous C3 activation and recognition of pathogen surfaces

C3/C3b

C3 and C5 Convertases

Pathway	C3 Convertase	C5 Convertase
Classical	C4b2a	C4b2a3b
Alternative	C3bBb	C3bBb3b
Lectin	C4b2a	C4b2a3b

Note: Some textbooks use different naming for the C2 fragments. Follow the notation used in your Parham course materials. The functional complex is commonly written C4b2a.

iC3 vs. iC3b and iC3Bb vs. C3bBb

Molecule	Status	Meaning

C3b

✅ Active

Functional complement fragment

iC3b

❌ Inactivated

C3b after regulatory cleavage

C3bBb

✅ Active

Alternative pathway C3 convertase

iC3Bb

❌ Inactivated

Inactivated form of the alternative C3 convertase

Key idea:
“i” = inactive/inactivated.

Factor I helps cleave C3b into inactive forms, helping stop complement activation.

Greatest Amplification

C3b

C3b provides major amplification because it can form the alternative pathway C3 convertase (C3bBb).

That convertase produces more C3b, which produces more convertase:

C3b → C3bBb → more C3b → more C3bBb

This creates a powerful positive-feedback amplification loop

Membrane Attack Complex (MAC)

MAC components:

C5b + C6 + C7 + C8 + C9

Written as:

C5b–9

C9 is the component that polymerizes to form the pore in the target membrane.

Memory:
C5b → C6 → C7 → C8 → C9

Complement Amplification Protein

Properdin (Factor P)

Question	Answer
What protein amplifies complement?	Properdin
Which pathway?	Alternative pathway
How?	Stabilizes C3bBb, the alternative C3 convertase
Result	More C3 is cleaved → more C3b

Properdin stabilizes the alternative pathway C3 convertase, extending its activity and increasing complement amplification.

Complement Inhibition

Complement can be inhibited at important points in the cascade, including:

1. C3 convertase formation/activity

2. C3b activity/deposition

Factor I

Factor I cleaves C3b → iC3b

C3b → iC3b

This helps prevent continued complement activation on host cells

three Pathways — Big Picture

Pathway	Initiated By	Early Components	C3 Convertase
Classical	Antibody–antigen complex	C1q → C1r/C1s → C4 + C2	C4b2a
Lectin	MBL binding microbial sugars	MBL → MASPs → C4 + C2	C4b2a
Alternative	Spontaneous C3 activation on pathogen surface	C3b + Factor B + Factor D	C3bBb

Where do they converge?

All three pathways converge at:

C3

The C3 convertases cleave:

C3 → C3a + C3b

This is important because C3b provides opsonization and amplifies complement activation, while the pathway continues toward C5 activation and the MAC.