ImmunOncology - La Mémoire and The Anātman

ImmunOncology – La mémoire and the anātman
Antonio Silvestro
Department of Agriculture, MSc Plant, Food Science and Environmental Biotechnology, University
Federico II of Naples, Portici (NA), 80026, Italy
Abstract:
A biotechnology educational paper illustrating the immune system and its involvement in tumor
proliferation, comprising with a new glimpse about the genesis of vaccination and the spontaneous
symbiotic reassembling that shaping humankind and its microbiome.
Keywords: immunology, oncology, HIV, biotechnologies, physics, quantum mechanics,
biomagnetisms, microbiome.
Correspondence to:
Antonio Silvestro, n°100 Nazario Sauro St., 80026 Casoria (NA) (Italia), 3382634244, antonio-silvestro@pec.it
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Google mail tonysilverxxx@gmail.com Sex Male | Date of birth 15 May 1992 | Nationality Italian
Introduction
Holistic approaches for perception, participation, ranking of health and environmental risk for
comprehensive scientific uncover divulgation of Nano-technology results would bridge the gap
between scientist and not; awakening young families in deal with children vaccination and for the
other hand to let it becomes affordable and sustainable, increasing the routine immunization
coverage helping poor infants worldwide still not reached to get it, for example, enhancing the low
25% Reoviridae Rotaviruses (group RVA) vaccine for gastroenteritis.
Antonio Silvestro, 2018
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Immune system (from Latin Immunitas - tax-free, exemption from burdens imposed by the state)
knowledge is fundamental in biotechnology for epitope analysis application. In 39-65 AD Marcus
Annaeus Lucanus during North-Africans colonisations manifested snake resistance, while some
century later in 430 AD Thucydides during the Yersinia pestis Athens epidemy discovered that an
individual can't get into an immune disease two times as validated by Procopius in 541 AD. One
thousand years later, Fracastoro proposed the immunization against the pest disease. In 1660 the
Royal Society divulgated the scientific knowledge about it. In 1714 Lady Montagne vaccinated her
children against the small-pox leaving them inhaling the dry pustules from the healed patients,
variolation later utilized also for the royal babies of king Giorgio I in 1721. Actually, is guessed that
vaccination originated in the ancient Goa, India as early as 1500 BC, the first inoculation of
anātman (no-self from Sanskrit) in a human body occurred, health process later mentioned in
occident by Voltaire during “Les Lumières period” writing about the Circassian beauties fluid
bumps administration, to the Western European first vaccine invention by Edward Jenner in 1796,
preventing parents experimenting a real fear, not the mere desire to know, inoculating a Poxviridae,
Orthopoxvirus, Cowpox virus pustules from Bos taurus cattle’s feeding, as I guess on Vaccinium
spp., to provide immunity to smallpox (dsDNA Variola virus) globally eradicated only in 1980 as
certified by World Health Organization (WHO).
Innate Immunity
The conserved innate immunity display itself in many matrices (e.g. skin, vaginal, bronchial, nasal
mucosa, saliva, tears) mediated by phagocytes with their typical protrusions, granulocytes
[(PolyMorphoNuclear leukocytes (PMN) – neutrophil, eosinophil, basophil, monocyte)]. This last
differentiate into macrophages in lymphoid tissues – spleen and lymphonods, liver (Kupffer cells),
gut, connective and circulatory tissues, containing lytic enzymes [(lysozyme, acid hydrolases,
elastases, collagenases, plasminogen activator factors (PAF)], reactive oxigen species (ROS) and
antibiotic proteins such as the globular lactoferrin [(80kDa, Chr.3(Homo sapiens)] in their
liposomes, releasing soluble mediator chitokinins [(e.g. INterFerons (INF-α, INF-β)], Tumor
Necrosis Factor (TNF-α), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF, G-CSF,
M-CSF), InterLeukin (IL-1, IL-6, IL-8, IL-10, IL-12), Transforming Growth Factor (TGF-α, TGF-β)
and Natural Killer cells (NK) eliminating oncotic and virus-transfected cells. Inflammation is just a
shallow deleterious effect of the natural immunity due to the off-target tissues involvement.
Among invertebrates, innate immunity is a defence mechanism against harmful non-self-agents. In

response to recognition of microbial pattern molecules, for example, Drosophila melanogaster
activates Toll-Like Receptors (TLR) or ImD pathway, leading the translocation of Nuclear Factor
kappa-light-chain-enhancer of activated B cells NF-kB (or Rel) transcription factors, from the
cytoplasm to the nucleus and the following peptide antibody production. TLRs evolved since
organisms acquire a body cavity, found from cnidarians to mammals, are characterized by an
extracellular Leucine Rich Repeat (LRR) domain and an intracellular Toll/InterLeukin-1 Receptor
(TIR) domain. Hence, the epidemic vector-borne diseases can be blocked in their spread researching
through innate immunity strategies (L. Zheng et al., 2005).
Pinocytosis (from Latina nova píno, to drink, and cytosis, proposed in 1931 by W.H. Lewis) is a
peculiar endocytosis in which the internalized substance is in a fluid state, on contrary from the
phagocytosis (from Ἑλληνική Hellēnikḗ φαγεῖν (phagein), meaning ‘to devour’, κύτος, (kytos)
‘cell’, and -osis ‘process’) characterized by a solid intake (bacteria, viruses or cell debris) mediated
by specific receptors.
Both neutrophils and macrophages can phagocyte, but they differ for their own amount, lifetime,
tissue location, time to reach the infectious site, number of lysosomes. The many neutrophils can
live from 3 to 5 months in the blood vessels phagocyting potential solid no-self particles, hence,
detectable according to their magnetic field – biomagnetisms, in few hours can be found in the
invaded tissues where a lot of lysosoms essudate their content; otherwise, the few macrophages
lives for months dispersed in many tissue phagocyting, but also manifesting specific antigene on
their surface (e.g. CD4 and CCR5 against the Human Immunodeficiency Virus (HIV)), they leave
the other PMN to carry out their activities, before processing themselves the wavy colonizers in
greater than or equal to one week. Valcyte (Valganciclovir ®) and Enfuvirtide (Fuzeon ®) are
fusion protein used HIV inhibitors.
Human Immunodeficiency Viruses (HIV), a Lentivirus ssRNA-RT group VI, capsid (⌀ = 120 nm ),
overtime cause Acquired ImmunoDeficiency Syndrome (AIDS), 9<Age survival estimated<11
years, sexual or parenteral breast milk transmitted. HIV-1,2 infects CD4+ TH via micro-tubular
transport integrating its two epistatic genomes (composed of 1000<NTDs<2000) into the target
host cell’s nucleus - lysogenic cycle characterized by a latent phase, killed by CD8 + Tc, via
(pyro)apoptosis, macrophages, microglial and dendritic cells.
7 HIV landmarks genome elements:

- Long Terminal Repeat (LTR)
- Trans-Activation Response (TAR)
- Rev Response Element (RRE)
- PE
- SLIP (Speckled-LIke Pattern)
- Cis-Regulatory Element (CRE)
- InSuliN (INS)
- Packaging Sequence Immunodeficiency (PSI)
Gen Protein Physiology

env gp160 proteolyzed by furin into allow to attach the target cell
gp120 and gp41 via virological synapses the
integrin α4β7 adhesion
Lymphocyte Function-
associated Antigen 1 (LFA-1)
gag p55 and p160 p24 bind to nucleo-capsid p7
and an integrin p17
pol DNA polymerase Polymerization
tat p16 and p14 Transactivation
rev p19 RNA shuttle by binding RRE
nef p27 CD4, MHC I and II receptors
down-regulated
vif p23 Prevent retrotrascription
interference
vpr p14 Arrest cell division at G2/M
vpu Viral Protein U accessory
HIV Tropism (Target cells):

- TH-tropic (T-tropic) SDF.1 downregulated the CXCR4 α-chemokines co-receptor;
- Macrophage-tropic (M-tropic) Central Nervous System (CNS), CCR5 β-chemokines;
- Dendritic cells can be transfected via both routes CD4 and CCR5 using mannose-specific C-
type lectin receptor such as DC-SIGN (Dendritic Cell-Specific Intercellular adhesion
molecule-3-Grabbing Non-integrin). The high genetic variability is ensured by 1010
virions/day, characterized by a high mutation rate= 3*10-5/NTDs replication cycle, reverse
transcriptase recombination and can be internalized via clathrin-coating endocytosis.
Immature high-mannose surface glycoproteins such as the gp41 isoleucine to proline (iso-L -> P)
amino acidic substitution are used as marker for crystallography and cry-electron microscopy.
While, SOSIP trimers, antigenic determinant with high-neutralising HIV epitopes.
Human transgenesis could be biotechnologically vehiculated by an HIV utilizing its infection

pattern to introduce a homeostatic preventive toolbox.
Adaptive Immunity
Adaptive immunity is induced by pathogens targeted by specific Antibody (Ab) (Immunoglobulin

Ig), glycoproteins in the Mucosa-Associated Lymphoid Tissues (MALT).
The immune portion of the lymphatic system that in its totality account the 2% of the body weight,
that is not ascribed to the blood circulation, is characterized by lymphocytes grown up in the fetus
liver and bone marrow (B) in Mammalia, while from the Bursa fabricii in Aves class, and
maturating in the Thymus (T) flowing in the lymph (from Latin lympha meaning ‘water’). The
component of the acquired immunity appear one week after the infection from a common precursor
of both B and T cells generated in the bone marrow. B cells mediate the humoral response
becoming antibody producers plasma cells, while helper T H and cytotoxic TC cells the cellular one.
Lymphocytes (⌀ = 8 m), 2x1012/adult man, 20%/leucocytes, heterochromatic nucleus with low
transcriptional level, almost without cytoplasm that can migrate through the circulatory system.
Smaller lymphocytes, with high N:C ratio, have a circular nucleus, while bigger a jagged core with
a low N:C ratio cyanophile granules. Sub-population can be distinguished by molecular markers on
their surface (immunoglobulins on the B cells) and T Cell Receptor (TCR). TH release cytokinin
(InterFeroN IFN-γ) that activated the B cells, others called lymphokines induced the migration and
activation of macrophages and their precursor monocytes, while the T C kill directly the targeted
cells, effectively, proteolytically digest the virus capsid coating themselves.
The main characteristics of the acquired immunity are:

- diversity: lymphocytes repertoire (e.g. T≥1015 cells). "The genetic principle for generation of
antibody diversity"(Susumu Tonegawa - Nobel Prize for Physiology or Medicine in 1987)
- specificity: glycol-proteinaceous antigen determinant (epitope) exposed, uniquely and
unequivocally, to the interstitial fluid, part of the inter-plasma lemma receptor protein.
- memory: a previous interaction between the immune system and the pathogen enhance the
response affinity.
- auto-limitation: e.g. programmed natural dead (apoptosis)
- discrimination between self and no-self, unobserved by the phagocytes during their development
leads to autoimmune diseases
The first successful Edward Jenner vaccine commercialization success has been followed by the
Louis Pasteur’s rabies vaccine in 1885, later on were developed to prevents other contagious illness:
anthrax, cervical cancer, cholera, diphtheria, hepatitis, influenza, measles, meningitis, mumps,
pertussis, plague, pneumonia, polio, rubella, tetanus, typhoid, tuberculosis, etc.
In 1890 Emil Adolf von Behring and Kitasato Shibasaburō (北里柴三郎) transferred the serum from
toxin diphtheria infected animals to healthy virgin ones immunizing them. In 1893 Elie Metchnikoff
found phagocytes on the scar tissues of an Echinodermata Asteroidae pinched by an Echinodae
predator spine. Phagocytosis myeloid – bone marrow cells relish the antigen via antibody
opsonisation (from the Greek opsōneîn, to prepare for eating). In 1900 occurred many immune
discoveries: Karl Landsteiner verified that the humoral response can be mediated by nonbacterial
substances, the same year Paul Erhlich formulated the “Humoral Theory” contemplating the physio-
chemical complementarity between antigen and antibody, “Opsonisation theory” were formulated
by Almroth Wright. Later on in 1942 Karl Landsteiner demonstrated the immunity acquisition
within the cell transfer and eight years later George Mackaness validated his data. The clonal
selection for which a lymphocyte clone pathogens-specific emerge from many precursors has been
theorized by Niels Jerne in 1955.
From the late 1960s onwards C. Milstein would devote much of his research investigating on
plasma cell cancer myeloma for understanding somatic mutation in antibodies on which is based
their diversity. In 1951 by Henry Kunkel found malignant plasma cells of multiple myeloma
appeared to produce just one antibody, instead of a vast array, nowadays cultivable in vitro. Dick
Cotton design an approach to produce antibodies with MOPC21 cell line in soft agar, displacing
five variants/7000 clones in three months of continuous culture, later fusing two myeloma lines
(sensitive to Bromodeoxyuridine and resistant) via Sendai virus manifested as and U-shaped
merged cell, the hybridoma. Between 1960 and 1962 Joseph Sinkovics come across a mouse
immunoresistant tetraploid lymphoma cell with virus-like particles on its surface causing a huge
tumours which presented as abnormal fluid or ascites in their abdomens. Later the mouse malignant
lymphoma was fused by the splenic plasma cells that acquired the immortal qualities.
Brigitte Ita Askonas generating E9 antibodies that bound to a hapten antigen by cloning B
lymphocytes storable for 6 months. By early 1975 Walter Gerhard, produced the antibodies
specificity against influenza viruses conservable for a maximum of only three months.
In 1973 Jerrold Schwaber and Edward Cohen fusing human B lymphocytes with mouse myeloma
cells created a humanized hybridoma specific-antibody producer capable to survive indefinitely.
C. Milstein and G. Köhler grown fusion tumour P3-X63-Ag8 cells in a Hypoxanthine-Aminopterin-
thymidine (HAT) petri dish medium targeting Sheep Red Blood Cells (SBRC) antigen visualizing
the neutralization with white spots, and later greenish hybrid cell producer of monoclonal antibodies.
Later, Giovanni Galfré increased the cell-cell fusion succes for generating immortal monoclonal
antibodies produced by hybridoma in Hypoxanthine-Guanine PhosphoRibosylTransferase (HGPRT)
medium lysing the plasmalemma using the PhosphoEthilenGlycol (PEG). From the afomentiored
milestones, immunotherapies through chemicals and engineered monoclonal antibodies have been
increased in richness and diversity.
The immunity can be subdivided according to the maximum serum antibody concentration evidence
into:
I) primary: after more than one week, [Ab I]max= 1 g/mL
II) secondary: in one month, [Ab II]max= 104 g/mL
Otherwise, into three phases:
- recognition (lag I)
- activation (exponential I -> II)
- effection (stationary II)
Microbiome, Human Anatomy and Solar System involution - The embedded

Hypothesis
The immunoglobulin E, the coating antibody, represent an evidence of integration of the

gastrointestinal system into the human body, as a blackbody that gave origin to the Solar System,
the viscera are imploded on itself, bringing the microbiome within, but doesn’t ablating the
omentum, originating an assembled “multicellular phagocytes” resembling, a vacuum cavity in

which primordial microorganism community lodge, connected to all the other anatomic system via
the plasma - the forth state of matter.
Iconography 1: Mathieu Lanlgois, 2017
Instead, one of the soldiers pierced Jesus side with a spear, bringing a sudden flow of blood and
water (Bible John 19:34). Thymus is a bilobated organ right on the heart in the thorax cavity, where
each lobe is separated by connective tissue in which is laid a cortico-medullar junction with
Interdigitated Dendritic Cells (IDC) and further subdivided in cortex, chitin-dermic derived, where
there are macrophages and immature thymocytes ripening interacting with the nurse, cortical and
epithelial cells and endodermic-raised medulla where are protected maturated T cells, dendritic and
Hassall corpuscles. This lymphatic organ is endocrine physiologically involved in the maturation of
the lymphocytes via Grow Factors (GFs) releasing, for example, by stromal medulla cells and has
also a screening function mainly due to the IDC. Mammal's thymus regress with the age, in Homo
sapiens atrophies beginning already with puberty continue for all the life; cortex completely
disappear due to corticosteroids hormones releasing in the circulatory system that see their dose
increase, for example, during pregnancy, while the medullar not fully.
In the bone marrow B cells maturated in strict association with reticular stromal cells. They can be
found in the omentum, the lipid membranous tissue that covers and supports the intestines. 75% B
cells overcome apoptosis, the left cells migrate in the secondary lymphoid tissues encapsulated into
spleen and lymph nodes or coagulated into MALT and its sub-groups [Gut, Bronchial, Nose, Larynx,
Eye, Vascular, Skin-Associated Lymphoid Tissue (G, B, N, L, E, V, S-ALT)].
Spleen, a connective capsule in which are dispersed trabecula’s is localized on the top left abdomen
systemically transport antigens through the circulatory vessels. Clusters of erythrocytes form red
parenchyma, while sites of antigen recognition are white. Other peripheral lymphoid tissue (2<⌀<10
mm), the lymph nodes filtrates the antigens flowing via the lymph in the neck, armpits, groin,
abdominal cavity and mediastinum drainer. Lymph nodes form the core till the periphery are
composed of the medulla, macrophages, paracortical T, germinal cells and cortical B cells.
Antigen-Presenting Cells (APC) are accessory lymphoid cells that can proteolysis the antigens, and
conjugate the peptides with class II MHC molecules on the cell surface where the complex may
interact with appropriate TCR. Naïve lymphocytes meet the antigen carried by the APC such as the
dendritic cells, pass through the efferent vessels into the lymph nodes proliferating and coming out
in few days as effector cells recycling via the circulatory system via the afferent channels if the bind
fails. At the confluence of the lymphatic vessels, lymph nodes drip the lymph in the internal organs
grouping in the thorax duct. Peyer plaque situated in the tender intestine villi are enveloped by an
Epithelium Follicular Associated (FAE) in which pathogens antigens coated are transported by the
M cells in which micro-folds lodge T, B, dendritic cells, and macrophages till the mucous.
Phagocytosis is a crucial process already evolved from unicellular Prokaria, while in multicellular
Eukarya immune system can be thought in antagonistic symbiosis within pathogens.
Immunodeficiency’s come up from the lack in the functional reservoir, whereas screening errors can
lead autoimmunity phenomena. Selective pressure has brought diversification of the pathogens in
extra- and intra-cellular bacteria, viruses and multicellular helminths., toxigenic bacteria are
antibody-targeted and cytokines enhance the macrophage activity.
All the antigens (Ag) (from Greek root anti-, ‘against’, and the word-forming suffix -gen, ‘things
that produces or causes’), exogenous or endogenous for autoimmune diseases, potentially induce an
immunity response culminating with a specific antibody linking dynamically with, electrostatic,
hydrophobic interactions, Van der Waals forces (e.g. Keesom, H-bonds, Debye, London) the epitope
site, acts as immunogen. Otherwise, haptens (<10.000 uma) alone cannot provoke an immunogenic
response needing a carrier. In 1921, Karl Landsteiner injected in a rabbit (Leporidae sp.) a horse
(Equus ferus caballus) kidney alcoholic extract without inducing an immune response, while
administrating a kidney homogenate the targeted organism produced antibodies, hence, determining
the presence of just a hapten in the first, while also a carrier in the second puncture.
Affinity and specificity are two parameters that determine the selectivity of an antibody for its
homologous antigen, a property that depends on the position, size, charge, and stereoisomers as
proved by amino acid substitution and cross-reactivity phenomena. An antigenic protein is
characterized by a molecular mass (M≥ 50 kDa), solubility, differentiating the utmost from the self-
molecules, dose concealing acquired tolerance and the immunologic memory.
In 1960 M. Sela studied the immunogenicity of diverse later amino acidic chains binding on a
lysine backbone, the epitope unfolding determinate the immunity manifestation. In the same years
Giacinto Tassi found domains in the wales (Cetaceae families) myoglobin capable to induce the
immune response and distinguished the linear epitopes, stiffened tightly binding by the antibodies,
continuous in the primary structure admitted both the T and B cells, from the conformational
antigenic determinants, where the amino acids are discontinuous in the primary sequence, but
contiguous in the tertiary, recognized just the B cells. Epitopes dominance is screened according the
Darwinian selection, variable second to somatic hyper-mutation, but mainly depends on the
antigens hydrophily and affinity.
B lymphocytes developed and ripened themselves in a 4 phase cycle:

I. totipotent STEM cells originated in the bone marrow (bm) matured into pro-B earlier, in which
the immunoglobulin surface is determined by the rearrangement on both chromosomes (2n) of the
5’DJ3’ gene segments Heavy (H) chain, while the functional re-assortment of the 5’VDJ3’ H chain
happen just on one chromosome of pro-B late, with no shallow antibodies shows. Later, in the pre-B
cell the expression of the μ chain together with a Light (L) chains analogue permit the exposition of
the H, rearranging the 5’VJ3’ segments of the L chain which k gene recombination isn’t productive
if occur in both chromosome, as for the pro-B-cells, and gene blend on the first, eventually on the
second otherwise the lymphocytes dye. The immature B lymphocytes display outward functional
IgM. CD45RA and CD19 memorized antigens activate the lymphocytes B proliferation, CD40
favour the cooperation between B and TH, μ appear still from the pre-B, while IgM and IgD are
typical of B mature. Ig heavy chains have both D and J regions.
II. Tolerant repertoire selection in bm.
II a. Insoluble antigens (e.g. Major HistoCompatability - MHC) binding induce apoptosis due to
clonal deletion.
II b. Soluble antigens (e.g. proteins) link determine functional paralysis (anergia).
II c. Maturation and displacement into the periphery.
III. Antigen contact in the lymphoid tissues and following activation of B memory cells in the
folliculum, via the cooperation with TH secerning cytokines (IL-4-5-6), class exchanger and
proliferating agents, related to the affinity screening regulated by dendritic interacting with B cells
via CD23 and CD19 (somatic hyper-mutation), furthermore, expressing CD40 and TCR B MHC II
binding.
IV. Plasma cells differentiation cytokines induced and antibodies release in the bm
Transcription factors E2 and OCT are express during all the cycle, lymphoid-specific recombinases
RAG1-2 just in pro and pre-B, N-nucleotide addition via Terminal deoxynucleotidyl Transferase
(TdT) in the pro-B state, NF-kB only in pro-B late.
Antibodies are complex glycoproteins characterized by four polypeptide chains, two Heavy (H) and
two Light (L) resembling a Y letter, in which each Variable Length (VL) arm covalently pair the
High-Variables (VH) at N-terminus binding it with disulphuric bridges, while in the Y body the
assembly of constant regions (C), and its crystalline Fragments (Fc) occur via a C-terminus
coupling. VH and VL can pair permitting the formation of a specific Fragment antigen binding (Fab)
site on which is based the antibody diversification. The cysteine enzyme papain, isolated firstly
from Carica papaya, proteolytically digest Immunoglobulin in three fragments (2Fab and 1Fc),
while the gastrointestinal pepsin breaking down the Ig release a F(ab)2.
Table 1: Note H chains can further sub-classified in:


The main functional immunoglobulin classes are: Ig A (gastrointestinal lumen, mammalian gland),
D, E, (digestive peripheral mucosa and skin), G (systemic and teratogenic), M (heart).
All are characterized by a monomeric C-region, but the IgA, secreted against antigens introduced
via the diet, can present a membrane portion dimeric and the IgM including pentameric.
Immunoglobulin can be structurally equal - isotypic (e.g. IgA and IgG) because the antibodies
follow the antigens escaping from the digestive lumen systemically through the circulatory system,
allotypic, differing for just some sequence in the D-region and idiotypic vary at the V-region.

The recognition of the pathogens at the antigen binding site formed by the VH and VL together
come about the aggregated immunoglobulins, leads to the conformational change of this last
anchored to the Fc on the macrophage surface. H chains contains homolog Greek keys motives of
100<amino acids<110 in a stable folded immunoglobulin main domain. Differently from the CH
composed of at least two domains DH and JH, CL region is only composed of one domain, JL. The
Regions Determining Complementarity (CDRs) basically depends on two regions, loop
HyperVariable (HV) and -sheet Framework (FR); in each variable domain exists 3 regions hyper-
variables localized on three external loops on which depend specificity and diversity.
Immoglobulin IgG1 IgG3 IgM IgE

main functions:
Heavy Chains g1 g3 m e
Molecular Weight 146 165 970 188
(kDa)
Serum level
(mean adult mg 9 1 1.5 5 x 10-5
ml-1)
Half-life in serum 21 7 10 2
(days)
Activation ++ +++ +++ -

pathways
Placental transfer +++ ++ - -
Binding to +++ ++ - -
phagocytes
High-affinity
binding to mast - - - +++
and basophil cells
Staphylococcal
Protein A + +/- - -
reactivity
A. Claman in 1961 injecting both T and B lymphocytes together with Ovis aries (erythrocytes) into
Mus musculus mice, antibodies are released. Later on Mitchell and Miller determined that
immunoglobulins are produced by matured B cells, administrating red globules into the cavies,
isolated leucocytes form spleen (splenocytes) and subdivided them in three sample: anti-k + C’,
anti-d + C’ and serum + C’ (C’ complement, 20 pro-enzymes cascade activated enhancing
phagocytes antibodies effect in few minutes), finding Jerne plaques just in the vials with anti-k
produced by plasma cells. Multivalent antigen cross-links bound IgE antibody on the mast cells
surface cause the exocytosis of histamine and other inflammatory mediators.
Major Complex of Histocompatibility (MHC I and II) are membrane glycoproteins expressed by a
high-polymorphic gene sequence almost ubiquitary crucial in the immune response and act as
antigen carrier for the TCR cognition. Granulocytes induced by interleukin IFN- can be coated
with MHC I receptors, characterized by transmembrane (1,2,3) non covalently bind to the 2-
microglobulin exposing viral peptides (8<amino acids<10) digested by lysosomal proteases poured
in the cytosol, processed via the Reticulum Endoplasmic (ER) and Golgi Apparatus and transported
on the surface, while MHC II manifested by monocytes, macrophages dendritical cells and B
lymphocytes, have a quaternary structure composed of transmembrane (1,2 and 1,2), atypically
covalently binding in their cleft protein fragment (13<amino acids<25) of bacterial origin
phagocyted or mediated-antibody internalized and later set out on the exterior. Co-receptors are
present on the TH and TC. MHC Homo sapiens analogue HLA (Human Leukocyte Antigens) are
encoded by co-dominant class I gene loci are just four (A, B, C and I), while the class II genes are
eight (e.g. DP, DQ, DR). MHC I are localized on the Chr. 6 p, while the conserved 2-
microglobulin is on the Chr. 15. Lymphocitary Coryomeningyte Virus (LCV) injected in H-2k mice
induce a fibroblast lysis, while Ectromelia virus not (Albert et al., 1989). MHC restriction I focalize
the Tc on the infected cells, avoiding the death of healthy cells exposing viral debris, while MCH
restraint II APC on TH. For example, CD4 on TH help the other immune cells to the response against
extracellular infectious sources spread, while Tc CD6 and CD8 kill internalized viruses. The
progenitors T cells migrate from the bone marrow where there will maturate, where mitotically
divide and differentiate themselves rearranging TCR genes and others coding from surface
glycoproteins involved in the effector function recognition. Coordinated biomarkers are expressed
leaving the lymphocytes clones manifest different screenable phenotypes according to restriction
MHC (positive picking) and self-tolerance (negative selection). Intrathymic lymphocytes ripening
from STEM cells, common to myeloid cells, is a process in which are take part plasmalemma signal
complexes such as ~ 30 x 103 TCR, CD3, CD4/8, CD25, CD44, MHC I and II. Up to 98% of
migrating thymocytes dye for apoptosis, while the last less than 2% move into the periphery.
Extrathymic maturation permit increasing immune response efficacy. Monovalent TCR are
structurally similar to bivalent Fab, but anchored on the T surface, on contrary to the last,
disappeared by the plasma cells; at any rate, each is characterized by two polypeptide chains in
which there are two shared domains in the binding site. TCR and CD3 Immunoreceptor Tyrosine-
Based Activation Motives (ITAMs) are intracellular signal chains. CD4, MHC I recognizer, are
characterized by 4D segments extracellular in series, while the reciprocally excluded the co-
receptors CD8, MHC II binding, a and b, in parallel. T cell activated by APC can kill infected
epithelial cells privilege the cellular turnover. Innate immunity pre-determine if the adaptive
response will lead to the lymphocytes helper differentiation in T H1 or TH2: viruses and bacteria
induce IL-1,2 secretion by dendritic cells that can activate the NK cells to produce INF-activating
CD4 differentiation in TH1 starting up macrophages and finally provoking B cells to realize IgG2a
and IgG3, while, worms (e.g. Nematoda, Platelminta), IL-4 inducer open the way to the TH2
distinctness involving B lymphocytes and neutralizer IgA production. T H1 response is
predominantly evolved in undeveloped countries where are frequent bacterial and viral childhood
infections, divergently the TH2 is abundant in industrialized nations where in vaccines, hygiene and
antibodies entail predominantly allergies and otherwise, the T H1 lymphocytes annihilate
autoimmunity diseases such as rheumatoid arthritis and multiple sclerosis. Intestinal microflora is
stimulated by Interleukin IL-10 secreted by food supplement genetically engineered bacteria,
paracellularly routed from the lumen to down-regulate T cell activation, increasing homeostasis and
decreasing pro-inflammatory response, restoring tolerance. Actemra/RoActemra first-class
humanized anti-IL-6 receptor antibody for rheumatoid arthritis.
Human T lymphocytes, NK cells-like lytic activity have been found efficient against
haematological malignancies (follicular lymphoma, multiple myeloma, acute and chronic myeloid
leukaemia) and solid tumours (renal cell, breast and prostate carcinomas), sampling more than 250
patients from Europe, Unites States and Japan (Jean-Jacques Fourniè et al, 2013). Rituximab
(Mabthera) and Obinutuzumab (Gazyva) are drugs to treat chronic lymphocytic leukaemia.
Chronic Lymphocytic Leukaemia (CLL) is the commonest in western countries, occurring in
elderly patients, characterized by genomic alteration that impair apoptosis of clonal B-cells
diagnosed by blood counts, smears and CD5 antigens B lymphocytes immunophenotyping
establishing two prognostic staging, the Rai and Binet system, predicting resistance to
chemotherapies in deletion of the short arm 17 chromosome (del(17p)). For physical fit patient is

utilized chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab, while for
unfit ones, treatment with anti-CD20 antibody (Obinutuzumab, Rituximab or Ofatumumab) plus
milder chemotherapy (Chlorambucil). When early relapse happens, Bendamustine (plus Rituximab),
Alemtuzumab, Lenalidomide, Ibrutinib or Idelalisib could substitute the previous agents
administered. Peculiarly patients with del(17p) or TP53 mutation can be treated with ibrutinib or
idelalisib and rituximab combined (Micheal Hallek, 2015). A common cutaneous T- cell lymphoma,
the Mycosis Fungoides (MF), closely related to the leukemic variant Sèzary Syndrome (SS), can be
treated in the early-stages with topicals corticosteroids, phototherapy (Psoriasin with UVA or UVB),
chemotherapy, radiotherapy and total skin electron beam therapy. Zelboraf skin cancer is due to the
B-RAF gene V600 mutation. Systemic approaches are used for refractory early-stage and advanced-
stage disease (IIB-IV) and include Bexarotene, Interferon-genetically engineerred, extracorporeal
photopheresis, histone deacetylase inhibitors, systemic chemotherapy, and allogeneic
transplantation. Encouragingly, three random phases trials are assessing Brentuximab, Vedotin, and
anti-CCR4 antibody, Mogamulizumab (Sean Whittaker et al., 2018).
Antigens internalization pathways
Dendritic cells can phagocyte in epidermal Langerhans cells and the lymphatic follicular and
interdigitated tissues. Macrophages can process bacterial antigens (e.g. Listeria monocytogenes) via
many phases: internalization via phagocytosis, phagosome and phagolysosome formation, antigen
MHC II complex, exocytosis and antigen fragment ornating. Otherwise, antibody-mediated
immunity is executed upon activation by APC binding directly or via MHC II the Ag (e.g.
ovalbumin) linked, in the first case to the B cells surface antibody receptors, in the second via TCR
and CD4-MHC II involving the TH cells. This last lymphocyte interacts with the mature B cell
stimulating them to proliferate via IL-2, finally differentiating in plasma cells systemically releaser
of antibodies that complexing with antigens activating the complement, enhancing the phagocytosis
by opsonisation and neutralizing toxins and viruses, hence, permitting the maintenance of the inner
homeostatic equilibrium and the intensification of defences. Differently from the humoral response,
the cell-mediated eliminate specifically pathogens, tumoral and transplanted abnormal cells.
Viruses-transfected cells are recognized by Tc, also stimulated by TH cells, but through the CD6-
MHC I-Ag-TCR complex activating them proliferation, displaying processed antigens, cytokines
secretion, phagocytosis stimulator IFN-, cytolytic perforins and DNA fragmenting lymphotoxins
production. B and T antigens cognition and proteolytic catabolism via proteasome occur differently,
exogenous within the lysosomes, which action can be inhibited incubating with clorokinin, related
to the elusive pathogen replication compartmentalization, extracellular vesicular (e.g. Streptococcus
spp., Mycobacterium spp.) or out of them, intracellular cytosolic, against viruses.
An assay to evaluate the macrophage processing against Listeria monocytogenes consist of a

macrophage paraformaldehyde fixation or sodium azide treatment, sonication together with the
pathogen for 60’, washing, T cell adding and consequent antigenic determinant processed
fragments macrophage surface binding despite their metabolic inactivity due to the fastening agents.
Infective viruses induce Tc proliferation in mice that don't recognize lysosomal antigens, on
contrary inactivated viruses. T-LC50 is reached at 10-3 mg/mL with antigen internalization
receptors-mediated or higher 10-2 mg/mL without brokerage.
Cathepsins B, D, L, activated by the pH decreasing (zymogens), change conformation maturing
inside the Reticulum Endoplasmic (RE), then proteolyze antigens MHC II bound via extracellular
pathways. Conserved peptides called Class II associated Invariant Chain Peptide (CLIP) can block
the a and b MCH II three in variables complexes peripheral cleft binding site. Human Leukocyte
Antigen like Major Histocompatibility Complex (HLA), retained in the endosomes, co-regulating
DO, DM, DR catalysing stereochemically and efficiently the CLIP replacement.

Multi-catalytic proteases forming the proteasome (28 subunits: e.g. MECL-1, LMP2, 7 coded by
MHC) brake-down cytoplasmic proteins after basic and hydrophobic residual induced by the IFN-.
Proteolysed antigens, RE transmembrane proteins, TAP1 and 2 complexed with Tapasin and
Calreticulin, through the ATP domain (ABC), bind the hydrophobic domain octapeptides actively
transporting them from the cytosol into the lumen as demonstrate by transfection experiments.
2-M, stabilized by the MHC, and later Calnexin bind I class. Immunity can be overcome via
endogenous antigen processing in the RE in which take part the HSV viral peptides blocker
canalized to the lysosomes for being breaking-down, while peculiarly the adenovirus retains the
MHC I inside the reticulum.
Immunology diagnostic, prevention and treatment technologies
Enzyme Linked Immuno Sorbent Assay (ELISA): antigenic determinant on the deepest of the wells,
as chelating sediment in an ocean solution, bind antibodies submerged, as inorganic minerals
dissolved, but with this immunologic approach the link is revealed by colorimetric organic catalyst
assessment, the phosphatase alkaline absorbance.
Cobas Bio Integra-Core II immunochemistry analyser Roche, is one of the most advanced tools
currently for system biology assessment useful also for immunologists panting to conduct, for
example, epitope - antibody ligation assay.
Flow cytometry - Fluorescent Activated Cell Sorting (FACS) can be utilized to count the immune
cells. The immunofluorescent assay is another method to identify antibodies, in which exiting light
is polarized to a fluorochrome bound to the antibody, that raising the quantum level to reflect
photons, among the emitted discrete package of energy the ones canalized into the laser,
characterized by a complex system of lenses are detected and profiled. Flow cytometry is a
technique relatively quick and versatile, during while a mixture of fluorescent antibodies labelled
cells streaming, impact with a laser beam, forward scattered, side dispersed into a red
PhotoMultiplerTube (PMT) and 45° diffracted into Green PMT, signal processed and plotted by a
CPU. Sub-populations, adsorbed onto magnetic beads antibody-coated, are paramagnetically
canalized through an iron mesh that fixes them when a magnetic field is applied.
Heterologous recombinant DNA protein technology like in plant-based vaccine was conceptualized
by Roy Curtiss and Guy A. Cardineau in 1986, patent application achieved using transgenic tobacco
plants (Nicotiana spp.) capable of expressing antigens of Streptococcus spp. as bio-fabric.
Furthermore, through molecular farming is possible to produce plantibodies such as the ones
patented by the Plant Biotechnology Inc. in Nicotiana spp. for cavity verified under clinical trials in
Homo sapiens – CaroRx. The same company, have been producing chimeric fusion antibodies:
Bacillus anthracis toxin receptors Tumour Endothelial Marker-8 (TEM-8) and Capillary
Morphogenesis Gene-2 (CMG-2) [e.g. CMG2-Fc (PBI-220)], Plasmodium falciparum Rh5 receptor
fused to human Fc, immunoadhesin DPP4-Fc for Middle East Respiratory Syndrome Coronavirus
(MERS- CoV) lung treatment, anti-Ebola virus antibodies, IgG1 (0.5<yield<3 g/kg) in Nicotiana
benthamiana biomass after vacuum-assisted agro infiltration. Other industry, the Large Scale
Biology Corp (LSBC) personalized vaccine direct to follicular B lymphoma produced through
characterization of immunoglobulins marker in the carcinogenic masses of lymphocytes.
The recent outbreak of yellow fever of São Paulo in Brazil perhaps could be strategically contained
integrating the 17D vaccination and the Sterile Insect Technique (SIT) blocking the transfection of
the arbovirus via Culicidae (Aedes spp. and Hoemogogus spp.) mosquito vectors, detecting the
viruses in the early stage testing the blood with a Polymerase Chain Reaction (PCR) or in the late
with Enzyme-Linked Immuno Sorbent Assay (ELISA).

Onco-trends and immunotherapies advances
According to the World Health Organization (WHO) statistic, with 3.7 million new cases and 1.9
million deaths each year, cancer represents the second weighted humankind burden in Europe after
CardioVascular Diseases (CVD). In 2018, 1.735.350 novel carcinoma cases and 609.640 tumor
deaths are projected to occur in the United States (USA). Racial death ratio disparity has been
detected with 14% higher in the black population than white. The overall cancer death rate relative
decline of 22% decrease from 215.1 to 168.7 on 100000 USA population for 10 years since 1991,
from 25 to 30% in Maryland, New Jersey, Massachusetts, New York, Delaware (Rebecca L. Siegel
et al., 2015).
In 1922, William Coley used an attenuated strain of (Mycobacterium bovis), the Bacillus Calmette–
Guérin, as vaccine against Bladder Tumor (BT) opening the way for the immunoncology. Recent
research advances have shed new light on the role the immune system plays in advance-stages
cancer.
Natural Killer cells (NKs) are targeted in vivo as effectors for tumour treatment, actually, NKs are
prototype innate lymphoid cells endowed with a potent cytolytic function that provide host defence
against microbial infection and tumours (M.G. Morvan and L.L. Lanier, 2016). Innate Lymphoid
Cells (ILCs) death of allogeneic and autologous undergo malignant transformation and microbial
infection. 5-15% of the Peripheral Blood Mononuclear Cell (PBMC) in humans contribute to
tumour immunosurveillance. Cancer infiltration by NK cells are favourable candidates for
prognostic factor in Non-Small Cell Lung Carcinoma (NSCLC), renal and colorectal tumour.
NK cells display profound functional alteration in the tumoral phenotypic profile of Non-Small Cell
Lung Carcinoma (NSCLC) primarily manifested (e.g. NKp46 marker) as degranulation inability
and INF- production (Sophia Platonova et al., 2011). Anti-PD-1/PD-L1, released by Tumour-
Infiltrating Lymphocytes (TILs), are established agents in the clinical management of NSCLC
patients predicting the immune response to Immune Checkpoint Inhibitors (ICI). The co-presence
of PD-L1 and CD8+ in the tumour microenvironment is correlated to the immune response to ICI
treatment in melanoma (Florence Monville et al., 2017). Vitiligo is a skin and hairs disorder due to
autoimmune-mediated melanocytes destruction by Tc. Melanocyte specific reactive CD8+ T cells
were identified by staining INF-γ and enzyme-linked immunospot assay after stimulation with five
peptides from gp100, four peptides from MelanA/MART1, and two peptides from tyrosinase.
Immunoscore is a tool for in situ immune cell infiltrates into tumours made by Halio seek company
developed CD8+ t cells and Programmed Death-Ligand 1 (PD-L1+) suitable for melanoma
treatment.
An investigation about the prognostic contribution of CD8+ TILs in NSCLC, conducted on a panel
of 197 patients with resected pulmonary adenocarcinoma revealed a loss (44%) of HLA-A, lower
(75%) of HLA-B/C and higher (70%) HLA-E decoding. The melanoma intracellular
immunomodulator HLA-E MHC have the capacity to bind inhibitory receptors CD94/NKG2A
significantly enhanced after metastasis in the NK and Tc expression by IFN- in a
metalloproteinase-dependent fashion (Laurent Derrè et al., 2006).
285 stages I-IV colon cancer patients analysed with a Tissue Micro Array (TMA) staining
immunohistochemically HLA I (HLA-A, HLA-B, HLA-C), non-classical HLA-E and HLA-G with
Foxp3 biomarker for predicting prognosis in colon cancer patients revealing an Overall Survival
(OS) and Disease-Free Survival (DFS) in tumours that lack in Human Lymphocytes Antigens
(E.C.M. Zeestraten et al., 2013). Colon tumour is induced by the over-expression of the Antibody-
Dependent Cellular Cytotoxicity (ADCC) immunosuppressive HLA-E. Cetuximab is an anti-

epidermal growth factor receptor monoclonal antibody that increases the colorectal cancer survival,
leaving the cells less susceptible to ADCC inhibited when binding 2-microglobulin (Estrella
Mariel Lavy et al., 2009).
NK can detect the lack of MHC I thanks to the expression in humans of Killer Cell
Immunoglobulin-like Receptor (KIR), coded by a polymorphic gene family epigenetically regulated
via DNA promoter methylation, and “senescent” CD-T cells, requiring Sp1 transcription factors,
implicated in cardiovascular diseases (Ying Liu et al., 2009). Different genes and alleles that rise
KIR haplotyping and specific recognition by HLA I. Otherwise, KIR inhibition occurs through
ImmunoReceptor Tyrosine-based Inhibitory Motives (ITIM) in cytoplasmic phosphorylation
domain by SHP-1 leading the NK inactive status, furthermore, repressed by the heterodimer
CD94/NKG2A receptor of the HLA-E derived leader peptides binder. Recently the Innate Pharma
company have been licenced the Lirilumab (IPH2102/BMS-986015) a fully human monoclonal
antibody that is designed to block the interaction between KIR2DL-1,-2,-3 inhibitory receptors and
their igands, activating the NK cells.
Immunosurveillance is evaded by tumour cells by shedding membrane ligands that bind to the
NKG2D activating receptor on NK cells and/or T cells, on contrary cancer sensibilization in Mus
musculus happen to block the MULT1 NKG2D receptor (Weiwen Deng et al., 2016). NKp30 and
NKG2D expression increase under an environmental stress of infective condition. Dysfunction of
tumour regressive and metastasis controller natural killer cells, peripheral blood p-NK, and
malignant mammary tumour-infiltrating Ti-NK accompanying human breast cancer development,
characterized by the NKp30 NKG2D, DNAM-1, and CD16 receptor activation decrement,
conversely increased by NKG2A inhibitory receptors (Emilie Mamessier et al., 2011). Kadcyla is a
combination of the targeted therapy Herceptin (Trastuzumab) and the chemotherapy medicine
emtansine, conjugated against breast cancer.
The innate immune cross-talk between NKs and eosinophils via Natural Cytotoxicity Receptors
(NCR) leads to the eosinophils death when cytokine-primed NKp46 and NKp30 are released (Silvia
Pesce et al., 2017). NK express CD16 a low-affinity receptor for Fc of Ig responsible for antibody-
dependent cell-mediated cytotoxicity (ADCC). NK activation and degranulation, via exocytosis of
perforins and granzymes in their granules and secretion of pro-inflammatory cytokines (IFN- and
TNF) and chemokines (e.g. MCP-1, MIP1-a,b, RANTES, lymphotactin and IL-8) and Grow Factors
(GM-CSF) are the molecular mechanisms that permit classify NK as potential antitumoral cells
(Laura Chiossone and Eric Vivier, 2018).
Ectonucleotidases CD39 and CD73 hydrolyse extracellular Adenosine TriPhosphate (ATP) to
Adenosine DiPhosphate (ADP) and Phosphate Inorganic (Pi) (ADPase activity) that inhibits CD4
and CD8 T-cell and NK-cells. CD39/CD73 pathway adjust the Treg immunosuppression; in cancer
specimens, CD39 in infiltrating lymphocytes, stoma and tumour cells is expressed as demonstrated
by flow cytometry of human cancer lines (Jeremy Bastid et al., 2014). CD73 is a key regulator of
cancer cells proliferation, migration and invasion in vitro, tumour angiogenesis and immune escape
in vivo (Zhao-wei Gao et al., 2014). A drug, Avastin ® (Bevacizumab) prevent the growth around
blood vessels instead acting as direct chemiotherapic. Expanded, recruited and polarized neutrophils,
poorly characterized compared with other immune cells in chronic inflammation, foster
angiogenesis and metastasis cancer (Wei Lang and Napoleone Ferrara, 2016).
CINtec (R) PLUS Cytology (Roche mtm laboratories A.G., Heidelberg, Germany), is a
Papanicolau (Pap) test, a dual-biomarker to simultaneously detect p16 and Ki-67 to provide a strong
indicator of the presence of transforming Human Papilloma Virus (HPV) dsDNA
(Papillomaviridae family) infection during the uterine cervical cancer.

Acknowledgments:
To my father “Memory doesn't vanish, but is transferred through the generations”.
The author has a keen interest in Research & Development, above all analytical
procedures for investigating biological phenomena, environmental risk
assessments and quality control of industrial products.
His holding a Bachelor's degree in Biological Sciences, got with the highest
marks, attending the “MSc Plant, Food Sciences and Environmental
Biotechnology” at University Federico II of Naples, Portici (NA), 80026, Italy.
He is gained an egregious laboratory dexterity attending an internship to the
Institute of Biomolecular Chemistry – National Council of Research (ICB -
CNR). This experience gave him the opportunity to work closely with an excellent team of
professionals researchers, after which he travelled in Switzerland, UK and Cyprus joining
Permaculture, Agro-Forestry, Aquaponics, Phytoremediation projects in countryside’s developing
communities, Organic Farms, helping in Garden design, Ecological and Wellness architectures,
increasing his awareness through healing Yoga and Shamanism retreats.
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