Mechanisms of Regulation and Dysregulation of the Immune System¶
Chapter 361 | Harrison's 22e · Part 11 – Rheumatology & Immunology · Chapter 361
Key Clinical Points¶
- Immune homeostasis requires a balance between protective immunity and the prevention of self-damage or overreaction.
- T-cell activation requires two signals: primary (MHC/peptide to TCR) and secondary (co-stimulation, primarily CD28 binding to B7-1/B7-2).
- Immune checkpoints (e.g., CTLA-4, PD-1) act as 'brakes' to prevent over-activation; their inhibition is a cornerstone of modern cancer immunotherapy.
- Cytokines are key soluble proteins mediating growth, activation, and inflammatory responses.
- Monoclonal antibodies targeting specific cytokines (TNF-α, IL-6, IL-17) are mainstay treatments for various autoimmune and inflammatory diseases.
- IVIg works by blocking reticuloendothelial cell function and immune complex clearance in conditions like ITP and Kawasaki disease.
- CAR T-cell therapy utilizes engineered receptors to bypass natural TCR limitations and target specific antigens (e.g., CD19) on malignant cells.
- Genetic mutations in genes like AIRE, FOXP3, and STATs lead to significant immune dysregulation and autoimmunity.
- Central tolerance occurs primarily in the thymus via T-cell deletion; peripheral tolerance involves anergy, inhibitory signaling, and Treg suppression.
- Specific autoantigens (e.g., GAD65, Myelin-basic protein) are linked to specific clinical conditions like Type 1 Diabetes or Multiple Sclerosis.
DEFINITION & CLASSIFICATION¶
• Anergy:
Definition (Harrison's 22e): A reversible tolerance mechanism in which the T or B cell is in an unresponsive state following an antigen encounter but remains alive.
• Chimeric antigen receptor T cells (CAR T):
Definition (Harrison's 22e): Synthetic hybrid receptors created by recombinant techniques that combine an extracellular domain, usually derived from an antibody single-chain variable fragment (scFv), with intracellular signaling domains from activating co-stimulatory molecules (from endogenous T-cell receptors [TCRs], CD28, or 4-1BB) that allow for retargeting of T cells to antigens on malignant cells.
• Checkpoint inhibition therapy:
Definition (Harrison's 22e): A form of cancer immunotherapy where antibodies against T-cell or antigen-presenting cell regulators of immune cell inhibition are used to activate cytotoxic T cells to kill tumor cells.
• Co-stimulation of T cells:
Definition (Harrison's 22e): A secondary signal that T cells require for activation following presentation of peptide antigen by major histocompatibility complex (MHC) molecules to TCRs on either CD4 or CD8 T cells. A prime mediator of co-stimulation is the T cell CD28 molecule binding to B7-1 (CD80, CD86) on antigen-presenting cells.
• Cytokines:
Definition (Harrison's 22e): Soluble proteins that interact with specific cellular receptors that are involved in the regulation of the growth and activation of immune cells and mediate normal and pathologic inflammatory responses.
• Immune homeostasis:
Definition (Harrison's 22e): Balanced protective immunity that does not overreact to pathogens and harm the host, and immunity that is not deficient and does not predispose the host to harmful infections or malignancies.
• Immunoediting:
Definition (Harrison's 22e): Process of immunity selecting clones of cancer cells with reduced immunogenicity resulting in tumor escape.
• Natural killer cells:
Definition (Harrison's 22e): Lymphocytes with cytotoxic potential for host cells must deliver an activating co-stimulating signal in addition to TCR ligation. To avoid responding to cells bearing self-antigens, T cells must also maintain immune tolerance.
• T-cell exhaustion:
Definition (Harrison's 22e): State of T cells when the persistence of antigen disrupts memory T-cell function, resulting in defects in memory T-cell function.
ETIOLOGY & PATHOPHYSIOLOGY¶
Mechanisms of Immune Tolerance¶
• Central Tolerance: Occurs in the Thymus. Mechanism: TCR editing by V(D)J, thymic negative selection, T-cell anergy and inhibitory signaling, and T regulatory cell differentiation.
• Peripheral Tolerance: Occurs in Peripheral Lymphoid Tissues. Mechanisms: ◦ T-cell competition for cytokines: IL-2, IL-7, IL-15, and peptide-MHC. ◦ T-cell growth dependence on co-stimulatory molecules (e.g., CD28 ligands). ◦ Suppression of T- and B-cell responses by T regulatory cells and TGF-β, IL-10. ◦ Regulation of T follicular helper cell differentiation and function.
• B-Cell Tolerance: Occurs in Bone Marrow. Mechanism: Immature B cell maturation arrest and deletion.
• Peripheral B-cell Tolerance: Mechanisms: ◦ B-cell growth dependence on TCR ligands. ◦ BCR modulation of plasma cell differentiation. ◦ Germinal center B-cell dependence on T follicular helper cells (CD40L, IL-21).
Genetic Basis of Immune Dysregulation¶
• Monogenetic Mutations: Several mutations lead to specific immune failures or autoimmunities (Table 361-1). ◦ RAG1, RAG2: Lead to severe combined immune deficiency (Omenn’s syndrome) with autoreactive T cells. ◦ AIRE: Deficiency leads to APECED syndrome (autoimmunity, polyneuropathy, candidiasis, ectodermal dysplasia). ◦ STAT-1/STAT-3: → STAT-1 deficiency → decreased IFN-γ, susceptibility to TB. → STAT-1 gain of function → chronic mucocutaneous candidiasis with autoimmune diseases. → STAT-3 deficiency → hyper-IgE syndrome (Job’s syndrome). → STAT-3 gain of function → lymphopenia, autoimmune cytopenias, diabetes, enteropathy. ◦ FcεRII, FcεRIII, C-reactive protein, complement receptor for C3bi (ITGAM or compliment receptor 3), COPA, tripeptidyl peptidase: Lack of removal of cell debris leads to systemic lupus erythematosus; COPA leads to autoimmune lung, renal, joint disease. ◦ AID (Activation-induced cytidine deaminase): Leads to Hyper IgM syndrome type 2, low IgA, IgG, and autoimmune cytopenias.
MANAGEMENT & TREATMENT¶
Cytokine Inhibitors¶
- TNF-α Blockade: Used in rheumatoid arthritis, psoriasis, Crohn’s disease, and ankylosing spondylitis. → Agents: Monoclonal antibodies (adalimumab, infliximab, golimumab), TNF-R Fc fusion proteins (etanercept), and IL-1ra (anakinra).
- IL-1 Inhibition: Inhibits pathogenic cytokines; soluble IL-1 receptor antagonist (anakinra) or other inhibitors.
- IL-6 Inhibition: Tocilizumab inhibits IL-6 activity.
- T-cell Differentiation & Signaling: Targeting IL-12, IL-23 (to inhibit T 17 CD4 T cell differentiation) or direct anti-IL-17 antibodies for psoriasis and psoriatic arthritis.
- IFN-γ Therapy: Used in the treatment of the phagocytic cell defect in chronic granulomatous disease.
Immune Modulatory Therapies¶
- Intravenous Immunoglobulin (IVIg): Mechanism: Blocks reticuloendothelial cell function and immune complex clearance. Indications: Immune cytopenias (e.g., ITP), Kawasaki disease, GvHD, MS, MG, GBS.
- Stem Cell Transplantation (SCT): Goal: Replace dysfunctional immune system with a normally reactive repertoire. Applications: SLE, MS, scleroderma. → Note: Patients homozygous for the 32-bp deletion in the CCR5 allele (Δ32) are resistant to HIV-1 strains using the CCR5 co-receptor.
- CAR T-cell Therapy: Mechanism: Uses engineered receptors (e.g., anti-CD19) to target malignant cells. Structure: Includes extracellular antigen recognition domain (scFv) and intracellular signaling/co-stimulatory domains (CD3ζ, CD28, or 4-1BB). Outcome: Leads to cell killing, proliferation, and cytokine release.
Checkpoint Inhibition¶
- Anti-CTLA-4: Blocks CTLA-4 to allow CD28 binding → Enhanced effector activity.
- Anti-PD-1/PD-L1: Blocks PD-1 interaction with ligands (PD-L1, PD-L2) → Prevents inhibition by SHP2 → Enhanced effector activity.
- Approved Agents (Table 361-2): → Ipilimumab (CTLA-4) → Nivolumab, Pembrolizumab (PD-1) → Atezolizumab, Durvalumab (PD-L1) → Relatlimab + Nivolumab (LAG-3 + PD-1) → Retifanlimab, Toripalimab (PD-1) for Merkle cell cancer.
KEY PEARLS & HIGH-YIELD POINTS¶
• Immune Checkpoint Balance: The balance between co-stimulatory molecules (e.g., CD28, OX40) and inhibitory checkpoints (e.g., CTLA-4, PD-1) is critical for immune homeostasis. → Blockade of these 'brakes' is a primary strategy in cancer immunotherapy.
• Autoantigen Specificity: Specific autoantigens are linked to distinct clinical syndromes (Table 361-4). → GAD65 → Type 1 diabetes, stiff-person syndrome. → Myelin-basic protein → Multiple sclerosis. → Citrullinated proteins → Rheumatoid arthritis.
• Monoclonal Antibody Utility (Table 361-5): A wide range of monoclonal antibodies are approved for both autoimmune diseases and malignancies. → VEGF inhibitors: Bevacizumab, Ramucirumab, Aflibercept, Ranibizumab. → IL-4Rα: Dupilumab. → FcεR: Omalizumab. → α-4 integrin: Vedolizumab, Natalizumab. → Complement inhibitors: Eculizumab, Pozelimab. → FcRn: Rozanolixizumab. → IL-1 inhibitors: Canakinumab, Rilonacept. → IL-6 inhibitors: Siltuximab, Tocilizumab. → BAFF inhibitor: Belimumab. → SLAMF7 inhibitor: Elotuzumab.
Reference Tables¶
TABLE 361-1 Monogenetic Mutations That Lead to Immune Dysregulation and Autoimmunity¶
Harrison's 22e, p.2786
| MUTATIONS AND FUNCTIONAL DEFICITS | DISEASES OR SYNDROME |
|---|---|
| RAG1, RAG2; lymphopenia with recombinase deficiency | Severe combined immune deficiency (Omenn’s syndrome) with autoreactive T cells |
| AIRE, deletion chromosome 22q11.2; decrease in central tolerance | Ch. 22q11.2: DiGeorge’s syndrome with autoimmune T cells AIRE: autoimmunity, polyneuropathy, candidiasis, ectodermal dysplasia (APECED syndrome) |
| STAT-1, STAT-3; modulation of type 1 interferons | STAT-1 deficiency: decreased IFN-γ, susceptible to TB STAT-1 gain of function: chronic mucocutaneous candidiasis with autoimmune diseases STAT-3 deficiency: hyper-IgE syndrome (Job’s syndrome) STAT-3 gain of function: lymphopenia, autoimmune cytopenias, diabetes, enteropathy |
| FcfRII, FcfRIII, C-reactive protein, complement receptor for C3bi (ITGAM or compliment receptor 3), COPA, tripeptidyl peptidase; lack of removal of cell debris |
FcfII, FcfIII, CRP, complement receptor for C3bi: systemic lupus erythematosus COPA: autoimmune lung, renal, joint disease Tripeptidyl peptidase II: susceptibility to bacterial, viral, and fungal pathogens |
| Activation-induced cytidine deaminase (AID); class-impaired B-cell development |
Hyper IgM syndrome type 2, low IgA, IgG, recurrent bacterial switch recombination; infections, autoimmune cytopenias, SLE |
TABLE 361-2 Summary of the Tumor Types for Which Immune Checkpoint Blockade Therapies Are Approved by the U.S. Food and…¶
Harrison's 22e, p.2787
| TUMOR TYPE | THERAPEUTIC AGENT | TARGET | FDA APPROVAL YEAR |
|---|---|---|---|
| Melanoma | Ipilimumab | CTLA-4 | 2011 |
| Nivolumab | PD-1 | ||
| Melanoma | Pembrolizumab | PD-1 | 2014 |
| Nivolumab | PD-1 | ||
| Non-small-cell lung cancer | Pembrolizumab | PD-1 | 2015 |
| Ipilimumab + nivolumab | CTLA-4 + PD-1 | ||
| Melanoma (adjuvant) | Ipilimumab | CTLA-4 | 2015 |
| Nivolumab | PD-1 | ||
| Hodgkin’s lymphoma | Nivolumab | PD-1 | 2016 |
| Atezolizumab | PD-L1 | ||
| Head and neck squamous cell carcinoma | Nivolumab | PD-1 | 2016 |
| Pembrolizumab | PD-1 | ||
| Melanoma (any BRAF status) | Ipilimumab + nivolumab | CTLA-4 + PD-1 | 2016 |
| Atezolizumab | PD-L1 | ||
| Hodgkin’s lymphoma | Pembrolizumab | PD-1 | 2017 |
| Avelumab | PD-L1 | ||
| Urothelial carcinoma | Avelumab | PD-L1 | 2017 |
| Durvalumab | PD-L1 | ||
| Urothelial carcinoma | Nivolumab | PD-1 | 2017 |
| Pembrolizumab | PD-1 | ||
| MSI-high or MMR-deficient solid tumors of any histology | Pembrolizumab | PD-1 | 2017 |
| Nivolumab | PD-1 | ||
| Pediatric melanoma | Ipilimumab | CTLA-4 | 2017 |
| Nivolumab | PD-1 | ||
| Gastric and gastroesophageal carcinoma | Pembrolizumab | PD-1 | 2017 |
| Durvalumab | PD-L1 | ||
| Renal cell carcinoma | Ipilimumab + nivolumab | CTLA-4 + PD-1 | 2018 |
| Dostarlimab | PD-1 | ||
| Melanoma | Relatlimab + nivolumab | LAG-3 + PD-1 | 2022 |
| Tremelimumab | CTLA-4 | ||
| Merkle cell cancer | Retifanlimab | PD-1 | 2023 |
| Toripalimab | PD-1 |
TABLE 361-3 Immune Tolerance Checkpoints in T- and B-Cell Immunity¶
Harrison's 22e, p.2789
| CENTRAL TOLERANCE | PERIPHERAL TOLERANCE |
|---|---|
| THYMUS | PERIPHERAL LYMPHOID TISSUES |
| – TCR editing by V(D)J | – B- and T-cell anergy and inhibitory signaling (CTLA-4, PD-1, and other checkpoint molecules) |
| – T-cell anergy and inhibitory signaling | – T-cell competition for IL-2, IL-7, IL-15, and peptide-MHC |
| – T-cell growth dependence on CD28 ligands and other co-stimulatory molecules | |
| – Suppression of T- and B-cell responses by T regulatory cells and TGF-β, IL-10 | |
| – Regulation of T follicular helper cell differentiation and function | |
| BONE MARROW | |
| – Immature B cell maturation arrest | – B-cell growth dependence on TCR ligands |
| – Immature B cell deletion | – BCR modulation of plasma cell differentiation |
| – Germinal center B-cell dependence on T follicular helper cells (CD40L, IL-21) |
TABLE 361-4 AUTOANTIGEN Cell- or Organ-Specific Autoimmunity Acetylcholine receptor Actin Adenine nucleotide translator…¶
Harrison's 22e, p.2790
| AUTOANTIGEN | AUTOIMMUNE DISEASES | AUTOANTIGEN | AUTOIMMUNE DISEASES | ||
|---|---|---|---|---|---|
| Cell- or Organ-Specific Autoimmunity | Aminoacyl-tRNA synthetase (several) | Polymyositis, dermatomyositis | |||
| Acetylcholine receptor | Myasthenia gravis | Cardiolipin | Systemic lupus erythematosus, antiphospholipid syndrome |
||
| Actin | Chronic active hepatitis, primary biliary cirrhosis |
||||
| Carbonic anhydrase II | Systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis |
||||
| Adenine nucleotide translator (ANT) | Dilated cardiomyopathy, myocarditis | ||||
| Collagen (multiple types) | Rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis |
||||
| β-Adrenoreceptor | Dilated cardiomyopathy | ||||
| Aromatic l-amino acid decarboxylase | Autoimmune polyendocrine syndrome type 1 (APS-1) |
||||
| Centromere-associated proteins | Systemic sclerosis | ||||
| Asialoglycoprotein receptor | Autoimmune hepatitis | ||||
| DNA-dependent nucleoside- stimulated ATPase |
Dermatomyositis | ||||
| Bactericidal/permeability-increasing protein (Bpi) |
Cystic fibrosis vasculitides | ||||
| Fibrillarin | Scleroderma | ||||
| Calcium-sensing receptor | Acquired hypoparathyroidism | ||||
| Fibronectin | Systemic lupus erythematosus, rheumatoid arthritis, morphea |
||||
| Cholesterol side-chain cleavage enzyme (CYP11a) |
Autoimmune polyglandular syndrome 1 | ||||
| Glucose-6-phosphate isomerase | Rheumatoid arthritis | ||||
| Citrullinated proteins | Rheumatoid arthritis | ||||
| β2-Glycoprotein I (B2-GPI) | Primary antiphospholipid syndrome | ||||
| Collagen type IV-α3-chain | Goodpasture’s syndrome | ||||
| Golgin (95, 97, 160, 180) heat shock protein |
Sjögren’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, various immune-related disorders |
||||
| Cytochrome P450 2D6 (CYP2D6) | Autoimmune hepatitis | ||||
| Desmin | Crohn’s disease, coronary artery disease | ||||
| Desmoglein 1 | Pemphigus foliaceus | Hemidesmosomal protein 180 | Bullous pemphigoid, herpes gestationis, cicatricial pemphigoid |
||
| Desmoglein 3 | Pemphigus vulgaris | ||||
| Histone H2A-H2B-DNA | Systemic lupus erythematosus | ||||
| F-actin | Autoimmune hepatitis | ||||
| IgE receptor | Chronic idiopathic urticaria | ||||
| GM gangliosides | Guillain-Barré syndrome | ||||
| Keratin-8 | Rheumatoid arthritis | ||||
| Glutamate decarboxylase (GAD65) | Type 1 diabetes, stiff-person syndrome | ||||
| Ku-DNA-protein kinase | Systemic lupus erythematosus | ||||
| Glutamate receptor (GLUR) | Rasmussen encephalitis | ||||
| Ku-nucleoprotein La phosphoprotein (La 55-B) |
Connective tissue syndrome Sjögren’s syndrome |
||||
| H/K ATPase | Autoimmune gastritis | ||||
| 17-α-Hydroxylase (CYP17) | Autoimmune polyglandular syndrome 1 | Myeloperoxidase | Necrotizing and crescentic glomerulonephritis, systemic vasculitis |
||
| 21-Hydroxylase (CYP21) | Addison’s disease | ||||
| IA-2 (ICA512) | Type 1 diabetes | Proteinase 3 (PR3) | Granulomatosis with polyangiitis (Wegener’s), Churg-Strauss syndrome |
||
| Insulin | Type 1 diabetes, insulin hypoglycemic syndrome (Hirata’s disease) |
||||
| RNA polymerase I–III (RNP) | Systemic sclerosis, systemic lupus erythematosus |
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| Insulin receptor | Type B insulin resistance, acanthosis, systemic lupus erythematosus |
||||
| Signal recognition protein (SRP54) | Polymyositis | ||||
| Intrinsic factor type 1 | Pernicious anemia | Topoisomerase-1 (Scl-70) | Scleroderma, Raynaud’s syndrome | ||
| Leukocyte function-associated antigen (LFA-1) |
Treatment-resistant Lyme arthritis | Tublin | Chronic liver disease, visceral leishmaniasis |
||
| Myelin-associated glycoprotein (MAG) | Polyneuropathy | Vimentin | Systemic autoimmune disease | ||
| Myelin-basic protein | Multiple sclerosis, demyelinating diseases |
Plasma Protein and Cytokine Autoimmunity | |||
| C1 inhibitor | Autoimmune C1 deficiency | ||||
| Myelin oligodendrocyte glycoprotein (MOG) |
Multiple sclerosis | ||||
| C1q | Systemic lupus erythematosus, membrane proliferative glomerulonephritis |
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| Myosin | Rheumatic fever | ||||
| p-80-Collin | Atopic dermatitis | Cytokines (IL-1α, IL-1β, IL-6, TNF-α, IFN-γ IL17A, IL-17F, GM-CSF) |
IL-1α, IL-1β: rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus; IL-6: bacterial infections; IFN-γ: bacterial infections, varicella- zoster virus reactivation; IL-17A, IL-17F: chronic mucocutaneous candidiasis; GM-CSF: pulmonary alveolar proteinosis, fungal infections |
||
| Pyruvate dehydrogenase complex-E2 (PDC-E2) |
Primary biliary cirrhosis | ||||
| Sodium iodide symporter (NIS) | Graves’ disease, autoimmune hypothyroidism |
||||
| SOX-10 | Vitiligo | ||||
| Thyroid and eye muscle shared protein |
Thyroid-associated ophthalmopathy | ||||
| Factor II, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, thrombin vWF |
Prolonged coagulation time | ||||
| Thyroglobulin | Autoimmune thyroiditis | ||||
| Thyroid peroxidase | Autoimmune Hashimoto’s thyroiditis | ||||
| Glycoprotein IIb/IIIg and Ib/IX | Autoimmune thrombocytopenia purpura | ||||
| Thyrotropin receptor | Graves’ disease | ||||
| IgA | Immunodeficiency associated with systemic lupus erythematosus, pernicious anemia, thyroiditis, Sjögren’s syndrome, and chronic active hepatitis |
||||
| Tissue transglutaminase | Celiac disease | ||||
| Transcription coactivator p75 | Atopic dermatitis | ||||
| Tryptophan hydroxylase | Autoimmune polyglandular syndrome 1 | ||||
| Tyrosinase | Vitiligo, metastatic melanoma | Oxidized LDL (OxLDL) | Atherosclerosis | ||
| Tyrosine hydroxylase | Autoimmune polyglandular syndrome 1 | Cancer and Paraneoplastic Autoimmunity | |||
| Systemic Autoimmunity | Amphiphysin | Neuropathy, small-cell lung cancer | |||
| Adrenocorticotropic hormone (ACTH) | ACTH deficiency | Cyclin B1 | Hepatocellular carcinoma | ||
| Aminoacyl-tRNA histidyl synthetase | Myositis, dermatomyositis | DNA topoisomerase II | Liver cancer |
TABLE 361-5 Monoclonal Antibodies Approved for Clinical Use in Autoimmune Disease, Some of Which Are Also Used in…¶
Harrison's 22e, p.2792
| TARGET MOLECULE |
FUNCTION | FDA-APPROVED mAbs, TRAPS, AND BISPECIFIC mAbs |
AUTOIMMUNE/ INFLAMMATORY |
MALIGNANCY | OTHER/COMMENTS |
|---|---|---|---|---|---|
| Cytokine that stimulates vasculogenesis and angiogenesis. Overproduced in some inflammatory disorders and tumors to induce increased blood supply. |
Bevacizumab (Avastin) Ramucirumab (Cyramza) Aflibercept (Eylea/Zaltrap) Ranibizumab (Lucentis) |
Age-related macular degeneration, macular edema, diabetic macular edema, diabetic retinopathy |
Colorectal cancer, nonsquamous NSCLC, breast cancer, glioblastoma, renal cell carcinoma, gastric cancer or gastroesophageal junction adenocarcinoma |
||
| IL-4 receptor alpha subunit |
Receptor that mediates IL-4 and IL-13-induced inflammation |
Dupilumab (Dupixent) | Atopic dermatitis (eczema), steroid- dependent asthma |
||
| Binds to mast cells, basophils, and other cells that express Fc-epsilon receptor and induces release of inflammatory cytokines |
Omalizumab (Xolair) | Asthma | |||
| Alpha-4 integrin | Alpha-4 integrin facilitates exit of inflammatory cells from blood into intestine or across the blood-brain barrier |
Vedolizumab (Entyvio) Natalizumab (Tysabri) |
Multiple sclerosis, Crohn’s disease, and ulcerative colitis |
IgG4 natalizumab therapy has been associated with PML caused by John Cunningham virus in immunocompromised patients. IgG1k vedolizumab may not be associated with PML. |
|
| Inhibits complement cascade |
Eculizumab (Solaris) Pozelimab (Vepoz) |
Prevents destruction of red blood cells by activated complement (paroxysmal nocturnal hemoglobinuria) Treats complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) |
|||
| FcRn | Delivers IgG antibodies to tissues |
Rozanolixizumab (Rustiggo) | Myasthenia gravis | IgG4. Rozanolixizumab binds to human neonatal Fc receptor (FcRn), thus reducing the concentration of pathogenic IgG autoantibodies. |
|
| Mutations in cryopyrin lead to overproduction of IL-1 and inflammatory disease; IL-1 also drives other inflammatory diseases |
Canakinumab (Ilaris) Rilonacept (Arcalyst)a |
Rare inflammatory syndromes, active juvenile arthritis, gouty arthritis |
|||
| IL-6 | Overexpression of IL-6 is associated with multiple malignancies |
Siltuximab (Sylvant) | Pseudo- malignancy: Castleman’s disease (similar to lymphoma) |
Murine/human chimeric IgG1κ | |
| Current approvals based on role of IL-6 in promoting inflammatory autoimmune disease |
Tocilizumab (Actemra) | Rheumatoid arthritis, polyarticular juvenile arthritis, juvenile idiopathic arthritis |
|||
| BAFF (tumor necrosis factor superfamily member 13b) |
Role in proliferation and differentiation of B cells |
Belimumab (Benlysta) | Systemic lupus erythematosus |
IgG1-γ/λ | |
| SLAMF7 triggers the activation and differentiation of a wide variety of immune cells (innate and adaptive immune response) perhaps primarily mediated by natural killer cells and myeloma cells |
Elotuzumab (Empliciti) | Multiple myeloma |