Immunity, Inflammation and Disease: What the Physician Should Know

  

    
 
    
T    Lymphocytes
    
B    lymphocytes
    
Comments
  
  

    
Receptors

      Complement

      C3b

      C4b

      Immunoglobulin
      
 
      
Sheep erythrocyte (E receptor)
    
 
      
-

        -

        -
      
 
      
+
      
 
    
 
      
+

        +

        +
      
 
      
-
    
Receptors mainly for IgM but also for IgA, IgG    and IgE

      Present on 60-65% of all circulating T    lymphocytes
  
  

    
Surface antigens/markers

      1a

      Immunoglobulin
      
 
      
CD3 (T3)
      
CD4 (T4)

        CD5 (T5)

        CD8 (T8)
    
 
      
+

        -
      
 
      
+
      
+

        +

        +
    
 
      
-

        +
      
 
      
-
      
-

        -

        -
    
Present on circulating lymphocytes and    involved in cell-cell cooperation

      Circulating T lymphocytes

      T helper/ inducer cells

      T suppressor cells

      T cytotoxic cells/suppressor cells
  

Table 1: Receptors and surface antigens present on T and B lymphocytes.

Polymorphonuclear granulocytes (neutrophils) originate from bone marrow derived myeloid cells, and circulate in the bloodstream. Neutrophils live for 6-20 h and constitute approximately 60% of the total number of leucocytes. They bear surface receptors for IgA, IgG and complement components. Neutrophils play a primary role in non-specific immunity by engulfing and digesting microorganisms, and their absence usually proves fatal [17]. Mast cells are present in the skin and mucosal surfaces, and basophils circulate in the blood, where they constitute 0.5 to 2% of the circulating leucocytes. Although direct proof of common origin is lacking both mast cells and basophils are involved in type 1 immediate hypersensitivity reactions, when they release inflammatory mediators following allergen binding to IgE on their surface. They also bear receptors for complement components. Circulating basophils show an increase in allergic disease states and are seen in secretions of patients with allergic rhinitis. Eosinophil granulocytes originate from myeloid precursors in the bone marrow and circulate in the bloodstream, where they constitute 2-5% of the total number of leucocytes, although they may account for up to 20% in individuals with immediate sensitivity diseases or helminth infestation. They live for 6-20 h and bear receptors for IgG and complement components. Thus their primary activities are to engulf and digest immune-complexes important against helminth infection, and the release of enzymes that are able to inactivate biologically-active substances such as histamine in type I hypersensitivity reactions [18].

Immunoglobulins

The basic Immunoglobulin molecule (Ig) comprises four protein molecules, two heavy chains and two light chains, with a variable Fab end (antigen binding end) and Fc (the constant end) that determines the properties of the molecule. There are five classes of immunoglobulin, IgG, IgM, IgA, IgD and IgE, each having a specialized function determined by its heavy chain. Following gene rearrangement, antigen activated B cells differentiate into plasma cells, which are designed for high protein production and secretion. Initially, the splicing of variable region genes onto the new heavy chain gene leads to the production of IgM. This immunoglobulin is expressed on the surface of the developing B cells and acts as a trigger to further cell proliferation. Subsequently ‘gene switching’ leads to the production of IgG and the other immunoglobulins. IgG is the most abundant and dominant antibody in the human body accounting for 85% of all immunoglobulins. Part of this is because of its long, albeit variable, half-life of 7-23 days, depending on the IgG subclass. Like three of the five types of immunoglobulin, IgG exists as a monomer. It is found chiefly in the blood and lymph. It has the unique ability to cross placenta in pregnant women, allowing it to protect the unborn fetus and newborn baby. Its main activities include enhancing phagocytosis in macrophages and neutrophils, neutralizing toxins, inactivating viruses and killing bacteria. The Fc portion of IgG can bind to NK cells to set in motion a process of an Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC), which can kill or limit the effects of invading microbes. This gives IgG a wide palette of functions, fitting for an antibody that is so prevalent in the system. It is usually the second antibody on the scene following closely behind IgM when an invader is present. IgM is a pentamer and is the first to be produced in an immune response. IgM has a short half-life (about 5 days) and makes up approximately 13 to 15 percent of serum antibodies. Importantly, it is also the first line of defence among its four antibody siblings, being the first immunoglobulin made during a typical immunological response. Because IgM is a pentamer, it has 10 epitope-binding sites, making it a fierce adversary. Its five Fc portions, like those of most other immunoglobulins, can activate the complement-protein pathway, and as a "first responder" is the most efficient type of antibody in this regard. IgM agglutinates invading material, compelling individual pieces to stick together for easier clearing from the body. It also promotes lysis and phagocytosis of micro-organisms, with a particular affinity for ousting bacteria. Monomeric forms of IgM do exist and are found chiefly on the surface of B-lymphocytes as receptors or sIg (as with IgD). Interestingly, the body has already produced adult levels of IgM by the age of nine months. IgA is a dimer and is secreted by mucosal plasma cells. It passes through the epithelium and resides in the gut ready to deal with ingested antigens. On passage through the epithelium, a polypeptide secretory component is attached to the immunoglobulin which helps prevent digestion by the gut enzymes. IgD is found attached to the surface of B-lymphocytes as a B-cell receptor (also called sIg), where it is believed to control B-lymphocyte activation and suppression in response to signals from immunoglobulins that are circulating in blood plasma. IgD may be a factor in the active elimination of B-lymphocytes by generating self-reactive auto-antibodies. While it seems curious that antibodies would ever attack the cells that make them, sometimes this elimination may control an overzealous or misdirected immune response, or take B-cells out of the pool when they are damaged and no longer synthesizing helpful products. In addition to its role as a de facto cell-surface receptor, IgD is found to a lesser extent in blood and lymphatic fluid. It is also thought in some people to react with certain haptens (antigenic subunits) on penicillin, which is likely why some people are allergic to this antibiotic; it may also react with ordinary, harmless blood proteins in the same way, thereby effecting an autoimmune response. IgE is the rarest of the five classes of immunoglobulins, accounting for only about 0.002 percent of serum antibody, or about 1/50,000th of all circulating immunoglobulins. Nevertheless, it plays a vital role in the immune response. Like IgD, IgE is a monomer and has two antigenic binding sites, one on each "arm." It has a short half-life of two days. It is bound to specific regions of mast cells which recognize the Fc region of the immunoglobulin molecule and basophils, which circulate in blood. As such, it is a mediator of allergic reactions and plays a role in hypersensitivity reactions. When an antigen binds to the Fab portion of an IgE molecule bound to a mast cell, this causes the mast cell to release histamine into the bloodstream. IgE also takes part in the lysis, or chemical degradation, of parasites of the protozoan variety ( amoebas and other unicellular or multicellular invaders). IgE is also made in response to the presence of helminths (parasitic worms) and certain arthropods. IgE also plays an indirect role in the immune response by galvanizing other immune components into action. IgE can protect mucosal surfaces by initiating inflammation which tends to cause pain and swelling, but renders the other immune benefits of enabling IgG, complement proteins from the complement pathways and white blood cells to enter tissues to confront invaders [19,20].

Specificity and Antigen Receptor Rearrangement (Diversity)

The complex and diverse immune system is genetically regulated by somatic generation of variations on the basis of a limited number of germ-line genes. Each germline cell in the body contains genes for immunoglobulin and also a T cell receptor. The genes are divided into sections designated V (Variable), D (Diversity), J (Joining) and C (Constant). The V, D and J regions contain different versions of the same genes. Gene rearrangement occurs during the lymphocyte development.

A single gene from each section is selected while the other genes are eliminated. The new V, D, J sequence is spliced onto the heavy chain gene. Since these joins are random, this process generates considerable diversity. This diversity is even greater in the case of the heavy chain genes in which the Variable Heavy (VH) genes combine with a D gene which comprises a hypervariable region which in turn recombines with one of a cluster of J gene. Further variation occurs by the association of different light chains with the heavy chains, and possibly by changes of the arranged immunoglobulin genes by somatic mutations in the course of B cell ontogeny, and the arrangement of the a and β chains of the T cell receptor. It should be noted that this rearrangement is random and does not require the presence of antigen. Antigen-driven proliferation occurs in the secondary lymphoid organs where the lymphocyte and its progeny are specific for a single epitope on an antigen. Throughout life a person is exposed to a wide variety of antigens and consequently produce antibodies with a corresponding wide range of specificities. Of some 1020 immunoglobulin molecules in the circulation there are an estimated 105 -108different specificities [21,22].

The lymph node ensures thorough mixing of antigen, immunocompetent cells and immunoglobulins The constant slow flow of lymph from the tissues back to the blood ensures that antigenic sampling by the immune system can be easily carried out. The sampling occurs in the lymph node sinuses, which are lined by histiocytes capable of trapping antigen, particularly when coated with antibody. Simultaneously blood carrying lymphocytes arrives at the node. The peripheral blood contains 2 x 109 lymphocytes/ml, 70% of which are T cells. The cells continuously recirculate from the blood to the lymph node, to the thoracic duct and back to the blood. Antigen carried in the lymph is highly likely to meet its specific lymphocyte, because the two flows meet in the lymph node. The post-capillary venules in the lymph node are lined by cuboidal epithelial cells and are the site of lymphocyte emigration from the cardiovascular to the lymphatic system. The mixing of lymphocytes with antigen leads to a second phase of proliferation and differentiation. Proliferation and differentiation of the B cells occurs in the germinal centre. Firstly, plasma cells are produced that migrate to the medulla, where they secrete large amounts of specific immunoglobulin. Secondly, memory B cells are produced ready to confront the antigen on subsequent exposure. The secondary immune response is characterized by the rapid production of IgG, because the clone of specific B cells has multiplied and the immunoglobulin genes have already switched from IgM to IgG transcription. T cells migrating through the node will proliferate and differentiate as well, but around the blood vessels of the paracortex. The specific T cells produced, unstimulated lymphocytes, immunoglobulin that leaves the lymph node at the medulla, return via the thoracic duct to the bloodstream and ultimately arrive at the tissue from which the lymph was draining. In most cases, antigens are stopped at the lymph node and prevented from further progress through the body. In some overwhelming infections, however, organisms will elude the first line of defence, enter the bloodstream and then the lymphoid tissue of the spleen becomes very important [23,24].

The spleen is essentially an enlarged lymph node with a very similar arrangement. The splenic lymphoid tissue (the white pulp) consists of aggregates of T cells and B cells arranged around the arterioles. The spleen has two main roles: mounting immunological reactions to blood-borne antigens in the systemic circulation and the removal of abnormal red blood cells [25].

Mucosa-Associated Lymphoid Tissue (MALT) present beneath the mucosa from the tonsils to the anus, is responsible for generating immune response to gut contents. Similar lymphoid aggregates can also be found in the respiratory tract. There are B and T cell areas similar to those found in the lymph node, but the B cells have a tendency to infiltrate the epithelium possibly as a way of sampling the antigens in the lumen as particularly seen with the secretory IgA antibodies from Peyer’s patches (Gut Associated Lymphoid Tissues (GALT)) in the terminal ileum [1].

Elimination of the Antigen

The foreign organism is eliminated by the immune system in conjunction with elements of the inflammatory process. The precise reaction varies according to the nature of the pathogen. If the whole cell is recognized as foreign, immunoglobulins will be directed against it and will bind to cell surface antigens. The binding of antibodies and antigens activates the complement system. Complement is a series of nine plasma proteins which become bound to antigen-antibody complexes in a specific sequence (cascade). The binding or fixation of complement results in either the lysis or engulfment by phagocytes of the antigen via the classical or alternative pathways respectively. In the classical pathway, if the binding is on the surface of a bacteria cell wall the final protein product, C9, is able to punch a hole in the membrane and lyse the cell. In the alternative pathway, complement has more important function in aiding the phagocytosis of material in a process of opsonization. Phagocytes, ( macrophages and granulocytes) , have receptors for the Fc component of immunoglobulin and the C3b component of complement. The presence of both of these proteins will render it liable to phagocytosis. In promoting the elimination of the pathogen, the T helper cells have a role in the B cell germinal centre reaction, and for stimulating monocytes to differentiate into macrophages. Cytotoxic T cells are able to kill other cells directly. When a cell becomes infected by a virus, components of the virus are expressed on the surface of the cell in association with the Human Leucocyte Antigen (HLA). The receptors on the cytotoxic T cell recognizes the virus on the HLA molecule and is stimulated to secrete perforins, which punch holes in the membrane similar to those produced by complement C9. The helper or cytotoxic functions are determined by the CD4 or CD8 molecules expressed near the T cell receptor [1,2,4].

Hypersensitivity (inflammatory) Reactions

Six types of hypersensitivity have been described. Types I, II, III and V are mediated by antibody and type IV and VI by cellular mechanisms. In practice, these reactions may not necessarily occur singly. For example type II–VI may be involved in producing autoimmune diseases. Type I reaction (reaginic/anaphylactic/ immediate hypersensitivity) is an allergic reaction produced within 30 min of exposure to a specific antigen e.g. house dust,, pollens, animal danders or moulds in certain genetically predisposed individuals who are said to be atopic. Prausnitz and Kustner in 1921, showed that the passive transfer of a serum factor (reagin) from an allergic person to the skin of a normal person could produce an immediate wheal and flare reaction in the latter in response to the allergen [26]. The mechanism entails the allergen stimulating B cells to produce specific IgE, with the aid of T helper cells. This IgE, which is allergen-specific binds to mast cells via their Fc receptor. On subsequent exposure, the allergen cross-links the surface bound IgE on the sensitized mast cell that triggers the mast cell to degranulate and release inflammatory mediators (histamine, prostaglandins, slow reacting substance (leukotriene SRS-A)) aimed at destroying the noxious substance. In Type II reactions ( cytotoxic/ membrane reactions), antibodies (IgG or IgM) are produced against antigens on the patient’s own cells. These antibodies interacting via their Fc regions and fixing complement as well as the effector cell can lead to autoimmune diseases, e.g. autoimmune anaemia. Antibodies can also ‘block’ a receptor site preventing its normal function e.g. insulin-resistant diabetes antibodies, or the IgG autoantibodies against the gastric acid-secretory parietal cells (intrinsic factor antibodies) found in pernicious anaemia. In Type III reactions (immune complex mediated hypersensitivity) there is a hypersensitivity reaction to the immune complexes when not removed by the reticuloendothelial system but deposited in the tissues. Complement is activated and results in inflammatory reactions leading to cellular damage. The soluble complexes are formed when the antigen is in excess as by injecting large amounts of heterogenic serum into the circulation causing ‘serum sickness’ or the precipitation by insoluble complexes when the antibody and antigen are equivalent or in an excess of antibody causing an ‘arthus reaction’ (a red, oedematous area at site of injection within 4-12h). Complexes are deposited in the bronchial walls in pulmonary asperigillosis, and in the vessels in erythema nodosum. Immune complex formation with a self- antigen occurs in the autoimmune disease such as Systemic Lupus Erythematosus (SLE); Low- grade persistent infection with a weak antibody response to a microbial antigen occurs with viral hepatitis B or staphylococcal infective endocarditis and repeated inhalation of an environmental antigen, e.g. moulds or animal antigen can produce an extensive allergic alveolitis such as farmer’s lung disease with the antibodies being IgG. Type IV reactions (cell- mediated/ delayed hypersensitivity) reactions) take more than 12 h to develop and can be produced in several ways. The cell recruitment is initially neutrophil in nature (within a few hours) and is followed by lymphocytes and macrophage infiltration (24-48 h). Type IV reactions can be transferred from one animal to another by certain types of lymphocytes but not by serum. The reaction is mediated by a) T delayed hypersensitivity cells (TD) that have become sensitized to a particular antigen previously and release lymphokines (MAF, MIF, Interferon) and interleukins (IL-1,-2,-3); b) T Cytotoxic cells (Tc), which directly damage infected target cells, e.g. virus- infected cells, allogenic cells or host cells in graft- versus host disease. Thus, Type IV reactions are seen in association with viral infections and the intracellular bacterial infections- tuberculosis, leprosy and brucellosis and cause severe tissue damage. They are also implicated in autoimmune diseases such as Hashimoto’s thyroiditis and homograft rejection. Type V reaction (stimulating antibody reaction) is an IgG directed against cell surface antigens that stimulate some cells instead of killing them. This is seen in the pathogenesis of neonatal hyperthyroidism as IgG stimulating antibodies directed against thyroid cells would be capable .of crossing the placenta, or Graves’ disease (hyperthyroidism) in adults where serum IgG behave like TSH and binds to the thyroid TSH receptor producing excessive stimulation of thyroid hormone production. Interestingly, Graves’ disease is associated with other autoimmune disorders such as pernicious anaemia and myasthenia gravis (acetylcholine receptor antibodies at the nicotinic neuromuscular junction). Interestingly, thymic hyperplasia is found in 70% of myasthenic patients below the age of 40, and a thymic tumour is found in in 10%. Type VI reaction (Antibody-Dependent, Cell- Mediated Cytotoxicity (ADCC) entails Killer lymphocytes (K cells) which lyse target cells coated with antibody. Being activated by antigen-antibody complexes, the K cells interact with the Fc region of cell-bound antibody, and destroy the target cells by the release of proteolytic enzymes. Type VI reactions are also involved in autoimmune diseases, tumour rejection and defence against helminthic parasites. Immuno-pharmacology includes the role of anti-inflammatory (e.g. corticosteroids), immunosuppressive drugs (e.g. corticosteroids, cyclosporine & tracolimus against T cells) and anti-lymphocytic sera in dampening these hypersensitivity reactions and the prevention of transplant/ graft rejection [1-4,27]

Tumour Immunology

The immunological mechanisms involved in cancer growth are highly complex, including tissue-resident and blood-derived cells. Tumour- infiltrating immune cells play a key role against cancer. However, malignant cells are capable of evading the immune response and establishing a very complex balance in which different immune subtypes may drive tumour progression, metastases and resistance to therapy [28]. Cancer cells make high levels of proteins that can switch off the checkpoint proteins in T cells and the T cells can no longer recognise and kill cancer cells. Drugs or antibodies that block checkpoint proteins (checkpoint inhibitors) would prevent the switching-off action of the cancer cells and the T cells can then find and attack the cancer cells. The checkpoint proteins CTLA-4 (cytotoxic T lymphocyte associated protein 4) and PD-1 (programmed cell death protein 1) are found on T cells, and PD-L1 are on cancer cells. The checkpoint inhibitors are used in immunotherapy of cancers but since they boost all the immune cells, and not the ones that target cancer, the overactive T cells can cause possible side effects such as fatigue, nausea, skin rash, pruritus, anorexia, diarrhoea, and breathlessness and dry cough from inflammation of the lungs. They also cause, liver, kidney and thyroid dysfunction [11,29,30]. The human immune system mounts natural endogenous response to highly immunogenic tumour cells through a series of steps, including the presenting of tumour antigens to T cells via Antigen-Presenting Cells (APCs), priming and activation of T cells in the lymph nodes, trafficking and infiltration of T-cells into tumour beds, recognition of cancer cells by T cells, development of antigen-specific effector and memory T cells, and humoral immunity, allowing effector T cells and other endogenous immune cells as well as tumour- effective antibodies to tumour to eliminate cancer cells [31]. Monoclonal antibodies made from hybridoma cells by recombinant DNA technology are routinely used in several fields including infections, and targeted cancer therapy. They may also help turn the immune system against cancer i.e. immunotherapy by marking cancer cells for better recognition and destruction. An example is rituximab, which binds to the CD20 on B cells and some types of cancer cells such as lymphomas, causing the immune system to kill them. Other monoclonal antibodies such as blinatumomab bring T cells close to leukaemia cancer cells by binding to both CD19 protein on the surface of leukaemia cells, and CD3, a protein on the surface of T cells which would facilitate the response and killing of the leukaemia cells by the T cells [32].

Innate Immune Response to Tumour Cells

Cancer cells can alter the steady state activity of all myeloid cells present in the tumour microenvironment by secreting IL-6 or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), that induce the recruitment of immature myeloid cells to tumour cells, as well as cell proliferation. Natural Killer Cells (NKL) can kill target cells without the need for prior activation. As many neoplastic cells lose the expression of MHC-I during malignant transformation which at normal levels inhibit NK cells, they continue to express ligands (e.g. glycolipid) that activate NK cells. This recognition mechanism further leads to the progression of anti- tumour immune response through the production of interferon-λ which activate a number of interferon- λ signalling pathways that enhances the killing of a proportion of the tumour, induces the production of chemokines that further recruits more cells in the innate immune system, activates macrophages that express tumoricidal products (reactive oxygen and nitrogen metabolites) and, Tumour Necrosis Factor (TNF) that activates endothelial cells and coagulation leading to tumour necrosis, and directly stimulates apoptosis. Moreover, the cytokines, IL-12. IL-15, and the type 1 interferons stimulate NK cells, which leads to proliferation and increased cytotoxic activity [32].

Adaptive Immune Response to Tumour Cells

Cytotoxic T Lymphocytes (CTLs) are the primary mechanism of tumour cell killing in adaptive immune response, which in many cases, requires the participation of APCs to present the relevant tumour antigen to the CTLs. MHC-I and-II molecules must be present to stimulate the production of CTLs. Typically, MHC-I APCs such as Dendritic Cells (DC), present antigen (tumour-derived peptides) to CD8+ T cells in the context of co-stimulation through CD80, CD70, and 4-1BB, as well as through Dendritic Cells (DC)-derived cytokines such as IL-12, type 1 interferon, and IL-15. CD8+ CTLs have been demonstrated in numerous different types of solid tumours in vivo and have been shown to cause tumour cell destruction in vitro. CD4+ T helper cells release cytokines, leading to the anti-tumour immune reaction. The Th 1- polarized CD4+ T cells secrete IL-2. TNF-a, and IFN-λ, which promote the development of CD8+ CTLs and the activation of macrophage cytotoxic activity. In addition, they can upregulate antigen processing and the expression of MHC-I and-II molecules in professional APCs such as macrophages and DCs. In contrast, Th2 polarized CD4+ T cells release cytokines IL-4,-5,-6,-10 and -13, resulting in T-cell-mediated cytotoxicity, enhance humoral immunity, and regulate the tumor-promoting activities of macrophages. In addition to the effector mechanism mediated by CTLs, the host immune system can generate specific antibodies against cancer antigens, which exert cytotoxic effect against the antigen-bearing tumour cells. Rather than recognizing only protein-derived antigens by T cell antigen receptors, antibodies can bind to multiple types of tumour antigens including polysaccharides, lipids and proteins. This enhances anti-tumour ability by broadening the number of tumour antigens that can be exploited for cytotoxic reactions. Mechanisms of antibodies mediated tumour cytotoxicity include antibody-dependent cell-mediated cytotoxicity (Type VI hypersensitivity reaction) and complement-mediated cytotoxicity [33]. Cancer vaccines against the tumour associated antigens may stimulate the immune system so that it recognizes the cancer cells as foreign and attacks the cells. Cancer vaccines are made with cells from the patient’s own tumour, modified in the laboratory and then returned to stop, destroy or delay the growth of cancer [34,35]. Combination of whole cell vaccine GVAX and mesothelin-secreting vaccine CRS-207 demonstrated an overall survival benefit in metastatic refractory pancreatic cancer patients [36]. Anti-Gal is the most abundant natural antibody in humans, comprising about 1% of immunoglobulins. The anti-Gal ligand is a carbohydrate antigen called a-gal epitopes which is exploited in cancer vaccines to increase the immunogenicity of Antigen-Presenting Cells (APCs). As cancer cells or Pancreatic Ductal Adenocarcinoma (PDAC) tumour lysates are processed to express a-gal epitopes vaccination with these components results in in- vivo opsonisation by anti-Gal IgG in PDAC patients [37]. The Fc portion of the vaccine- bound anti-Gal interacts with Fc receptors of APCs, inducing uptake of the vaccine components, transport of the vaccine tumour membranes to draining lymph nodes, and processing and presentation of Tumour-Associated Antigens (TAAs). It also elicited strong antibody production against multiple TAAs contained in pancreatic ductal adenocarcinoma cells and induce activation of multiple tumour-specific T cell [37,38]. Murine dendritic cell, loaded with pancreatic tumour-specific glycoepitope C-ter-J28+, induces efficient anticancer adaptive immunity and represents a potential adjuvant therapy for patients afflicted with PDAC [39].

Conclusions

The immune system is complex, dynamic and integrated in function so as to fight against foreign substances (antigen) such as infection and cancer. The results of the response are not only to eliminate the foreign material through humeral (antibodies) and cell -mediated mechanisms, but, to confer protection against future contact with the antigen through memory B and T cell formation, and that forms the basis of passive and active immunity (vaccinations). The improving knowledge of the immune system has expanded the role of immunotherapy and vaccine therapy in oncology. However, the immunodeficiency diseases, autoimmune disease and the hypersensitivity reactions remain the major short-comings of the immune response.

Author Statements

Acknowledgement

We acknowledge the late Professor Anomah Ngu for his pioneering work on immunotherapy and vaccination for HIV/ AIDS, and along with the late Professor Beltus Bejanga remained the authors’ mentors in the practice of surgical oncology in Cameroon.

Conflict of Interest

The authors declare no competing interests.

Author Contributions

EPW was the main author, EN contributed to literature search

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restriction.

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